Green chem.: a series of spiro-epoxidized indole derivatives were synthesized by the multi-component series reaction of Professor Hu Wenhao, Sun Yat sen University

Spirocyclic indole skeletons are widely found in natural products and drug molecules, such as coerulescine (II), (+) - elaconine (III), rhynchophylline (IV), alkaloids (VI), and alkaloids aspergillines a, B (VII), which are natural products with good biological activity; horsfiline (I) and xen907 (V) as hna1.7 It is also a promising candidate drug (Fig 1) Because of the importance of their biological activities, spirocyclic indole skeletons have attracted wide attention in the field of organic synthesis However, at present, the direct production of spirooxyindole from indigo is still rare Recently, Professor Hu Wenhao's research group of Sun Yat sen University has developed a multi-component series reaction They use indiorene malondinitrile / 2-cyanoacetate to capture the protonated onium ylide, and then carry out intramolecular cyclization In the "one pot" reaction, they can get spirooxided indole derivatives The solvent used in this method is environmentally friendly and the catalyst can be recycled, which provides important enlightenment for green chemistry Relevant research results were published on Green Chemistry (DOI: 10.1039/c9gc01751h) (source: Green Chemistry) in the early stage of the study, the author studied the multicomponent reaction of diazoacetate (2a) and indiorenylprotonitrile (5a) in water and dichloromethane The final product 6A was obtained by intramolecular cyclization of ylide hydroxyoxyonium and indionenylpronitrile via Michael type addition, and the yield was 87% (Table 1, entry 1) Then the author screened a variety of catalysts and found that Cu (OTF) 2 had the best reaction effect When EtOAc was used as solvent instead of DCM, the yield was 98%, and the reaction system was more green (ENTIES 2-13) (source: Green Chemistry) under the best reaction conditions, the author first investigated the applicable range of indigo substrate (Table 2) The corresponding product (6B - 6g) can be obtained from the indigo derivative with electron donor and electron acceptor at 5-position 4 The 6-and 7-chloro-indirubin were also suitable substrates, and the product (6h-6j) was obtained in 90-94% yield When ethyl cyanoacetate (4b) was used instead of 4A, 6K and 6L were obtained (source: Green Chemistry) then, the author investigated the substrate range of diazo esters (Table 3) When Cu (OTF) 2 / Rh 2 (OAC) 4 is used as co catalyst, the diazo ester substituted by α - alkane (aryl) can be efficiently reacted to obtain 6 m – 6p in 52-82% yield The product 6q and 6R can also be obtained from diazoacetate with R 3 group change (source: Green Chemistry) finally, based on the mechanism experiment and related literature, the author proposed the possible mechanism of the multi-component series reaction (scheme 1) Firstly, carbene A is produced by the decomposition of α - diazo ester 2 Catalyzed by Cu (OTF) 2 or Rh 2 (OAC) 4 Then a reacts with H 2O to form ylide in the form of B 1, B 2 and B 3 If it is not captured by the active electrophilic reagent, B 2 is easily converted to alcohol 7 by 1,2-H shift When electrophilic reagent 5 is added, it can capture highly active intermediate B 2 to produce Michael type addition product C, which undergoes delayed proton transfer to form D, and then through intramolecular nucleophilic addition of hydroxyl group and nitrile to obtain mesomeric E Finally, the product 6 was formed by tautomerization of E (source: Green Chemistry) in a word, Professor Hu Wenhao's research group has developed the "one pot" reaction of Cu (OTF) 2 catalysis or Cu (OTF) 2 / Rh 2 (OAC) 4 co catalysis for α - diazo ester, water, indigo and malondialdehyde / cyanoacetate A series of spirocyclic indole derivatives were synthesized in 60-99% yield Water plays a dual role in the reaction It is not only a reactant providing hydroxyl source for the end product, but also a solvent to increase the reactivity and promote the recycling of catalyst In addition, the yield of the catalyst Cu (OTF) 2 will not decrease after being reused for 4 times.