ACS catalyst: metal catalyzed (4 + 3) cyclization of vinylazacyclopropane with p-benzoquinone methylate derivatives

Vinylazacyclopropane can form the metal intermediate of zwitterion π - allyl under the catalysis of metal, which can form the nitrogen carbon (NCC) framework in the cyclization reaction Many five membered and six membered nitrogen heterocycles were formed by (3 + 2) and (3 + 3) cyclization of vinylazacyclopropane However, there are few reports on the construction of seven membered rings by (4 + 3) cyclization Therefore, it is very challenging to realize the (4 + 3) cyclization of vinylazacyclopropane Recently, Professor Shi Feng and Associate Professor Mei Guangjian of Jiangsu Normal University reported the iridium catalyzed (4 + 3) cyclization of vinylazacyclopropane with p-quinone methylate (p-qm) derivatives, which constructed benzoxazol skeleton in medium to excellent yield and had high enantioselectivity In addition, in the presence of palladium catalyst and chiral ligands, the asymmetric (4 + 3) cyclization was realized and the chiral benzoxazoles were obtained The overall reaction has medium and high enantioselectivity Relevant articles were published in ACS catalyst under the title of "metal catalyzed (4 + 3) circulation of vinyl aziridines with para - quinone methide derivatives" In order to realize the (4 + 3) cyclization of vinylazacyclopropane, the author designed the reaction mechanism (scheme 3) Under the action of alkali, o-HYDROXYPHENYL substituted p-benzoquinone methylate derivatives become highly nucleophilic oxygen anion compounds At the same time, under the action of metal catalyst, vinyl azacyclopropane forms the zwitterion π - allyl metal intermediate a, and oxygen anion attacks a to get the intermediate B After that, the (4 + 3) cyclization of B was completed by intramolecular addition of 1,6-azadiazepine (source: ACS catalyst.) in order to verify the feasibility of the reaction, the author explored the reaction conditions with p-benzoquinone methylate derivative 1a and vinyl azacyclopropane 2A as substrates (table S1) Using PD 2dbq 3 · CHCl 3 as catalyst and CS 2CO 3 as base, the product (±) - 3AA was obtained The enantioselectivity was 80:20 Dr, but the yield was only 36% This preliminary result shows that the author's design is feasible Then the catalyst, alkali, solvent and temperature were further selected The results showed that [IR (COD) Cl] 2 as catalyst, DMAP as base and DCM as solvent, the best yield (95%) and enantioselectivity (93:7 DR) were obtained (source: ACS catalyst.) after obtaining the best reaction conditions, the author studied the applicability of (4 + 3) cyclization (Table 1) The R 1 substituent on the benzene ring of substrate 1 can realize the (4 + 3) cyclization reaction whether it is the electron absorption group or the electron supply group, and the reaction can obtain the medium to good yield (45-96%) and good to excellent enantioselectivity (75:25 - > 95:5 DR) (entries 1-13) From the reaction results of 1b, 1F and 1I, it can be seen that methoxy substitution can improve the reaction yield (entries 2, 6 and 9) By changing the substituents on the substrate 2-phenylsulfonyl group, the author found that the substituents for electron, electroneutral and electron deficient can make the cyclization of (4 + 3) go on smoothly, and (±) - 3 can be obtained with medium to excellent yield (50-95%) and excellent non enantioselectivity (89:11-93:7 DR) (source: ACS catalyst.) after the realization of (4 + 3) reaction, the author began to explore the asymmetric catalytic mode of this reaction (table S2) At first, under the catalysis of [IR (COD) Cl] 2 and chiral ligand L1, the model reaction of 1a and 2A produced almost racemic product 3AA After that, the author found that the transition of metal catalyst from iridium complex to palladium complex can improve the enantioselectivity of the product The results show that L1 is the best ligand to control enantioselectivity In order to improve the yield and enantioselectivity, a series of reaction conditions such as solvent, reaction temperature, alkali and catalyst were selected The results show that 3AA can be obtained by reaction of 1a and 2A at 20 ℃, with PD 2 (DBA) 3 · CHCl 3 as catalyst, L1 as ligand, CS 2CO 3 as base, CH 3CN as solvent The yield is 65%, the enantioselectivity is 83:17 DR and the enantioselectivity is 96:4 er (source: ACS catalyst.) Summary: iridium catalyzed cyclization of p-benzoquinone methylate derivatives with vinylazacyclopropane (4 + 3) was carried out Benzoxazol was synthesized in 40-96% yield and 70:30 - > 95:5 Dr non enantioselectivity In addition, the asymmetric (4 + 3) cyclization in the presence of palladium catalyst and chiral ligands has been realized The obtained benzoxazoles have moderate and high enantioselectivity.