Synthesis of pyrrolizine by the bicyclization of oxime ester and olefin catalyzed by organic iron

Imine radicals are valuable intermediates for the synthesis of N-heterocyclic compounds The formation of imine radicals can be realized by the homolysis of N-X bonds In the 1990s, zard completed some pioneering work (scheme 1, EQ 1) by using intramolecular cyclization / β - olefin addition series reaction of imine radicals Later, narasaka reported the transition metal catalyzed or single electron transfer induced N-O bond breaking reaction of oxime ether or ester So far, the development of imine radicals has attracted the attention of chemists The regioselectivity of free radical and olefin addition depends on the stability of free radical intermediates to a great extent Therefore, it is very difficult to generate α - selective free radical addition on β - functionalized Michael receptor (scheme 1, EQ 2) (source: org Lett.) recently, Kazuhiro Okamoto and his colleagues at Kyoto University, Japan, reported for the first time a scheme 1 method for the synthesis of pyrrolizine derivatives by iron catalyzed imine radical mediated bicyclization The reaction has good regioselectivity and substrate applicability, and has potential application value in the field of natural product synthesis or drug discovery Relevant research results were published in org Lett (DOI: 10.1021/acs.orglett.8b01073) Firstly, the reaction conditions were screened with oxime ester 1a and β - phenylenone 2A as substrates (Table 1) When 5 mol% FeSO4.7H2O was used as catalyst and 5 mol% dtbpy as ligand, the target product tetrahydropyrazine 3A (entry9) was obtained in 82% yield and 6.0:1 Dr value after 12 hours reaction at 120 ℃ After that, the author confirmed the structure of two non enantiomers by X-ray crystallography analysis (Figure 1) (source: org Lett.) (source: org Lett.), then, the author screened the applicability range of 1,2-disubstituted olefins (Table 2) The alkenes with electron rich or electron deficient aromatic groups at β - position can react with 1a, and the alkenes substituted by electron deficient aromatic group can obtain better reaction yield and enantioselectivity When the β - position of olefin is substituted by methyl, only 13% yield can be obtained Alkenes substituted by ketones, esters, amides, cyanogens and other electron absorbing groups at a position can also react successfully with 1 A to obtain the target compounds The author found that the reaction can be well carried out in gram scale (scheme 3) (source: org Lett.) (source: org Lett.) next, the author expanded the range of oxime ester substrates (scheme 4) When R 1 is methyl, 3ba can be obtained in medium yield, and when R 2 is methyl, a mixture of three enantiomers can be obtained When R3 and R4 are substituted by Spiro, methyl or hydrogen, the reaction can also proceed smoothly, and the target product can be obtained in medium yield (source: org Lett.) the compound 5A was isolated by adding the free radical trapping agent tempo in the reaction system It was proved that the imine free radical produced by the N-O bond homocleavage took place intramolecular cyclization In order to elucidate the origin of H atom at C-5 of pyrrolizine, heavy water (D2O) was added to the reaction system NMR analysis showed that most of the hydrogen at C-5 site of the target product was deuterized It was proved that the hydrogen at C-5 site mainly came from external protons, such as water in catalyst or solvent, rather than intramolecular transfer of hydrogen atom (source: org Lett.) further, the author proposed the reaction mechanism (scheme 5): under the action of iron catalyst, the N-O bond breaks in 1a to obtain intermediate a; then 5-exo cyclization and α radical addition of olefins to obtain intermediate D, which can be obtained by radical cyclization / oxidation or oxidation / cation cyclization Finally, the final product is obtained by deprotonation and protonation DFT calculation results show that the α addition of olefins has lower activation energy than β addition (source: org Lett.) finally, the author made a progress in the derivatization of product 3AA (scheme 6) Pyrrolizidine can be obtained by dqq oxidation of 3 AA or reduction of sodium borohydride, which further proves the practical value of the reaction (source: org Lett.) conclusion: Kazuhiro Okamoto, Kyoto University, Japan and his colleagues reported for the first time the iron catalyzed bicyclization of oxime esters with active olefins, providing an efficient and direct method for the synthesis of pyrrolizine derivatives The reaction has good regioselectivity and substrate applicability, and has potential application value in the field of natural product synthesis or drug discovery.