Iron‐Catalyzed Radical Relay Enabling the Modular Synthesis of Fused Pyridines from Alkyne‐Tethered Oximes and Alkenes

Abstract

We have rationally designed a new class of alkyne‐tethered oximes and applied them in an unprecedented iron‐catalyzed radical relay protocol for the rapid assembly of a wide array of structurally new and interesting fused pyridines. This method shows broad substrate scope and good functional‐group tolerance and enabled the synthesis of several biologically active molecules. Furthermore, the fused pyridines could be diversely functionalized through various simple transformations, such as cyclization, C−H alkylation, and a click reaction. DFT calculation studies indicate that the reactions involve cascade 1,5‐hydrogen atom transfer, 5‐exo‐dig radical addition, and cyclization processes. Moreover, preliminary biological investigations suggest that some of the fused pyridines exhibit good anti‐inflammatory activity by restoring the imbalance of inflammatory homeostasis of macrophages in a lipopolysaccharide‐induced model.

Iron‐Catalyzed Radical Relay Enabling the Modular Synthesis of Fused Pyridines from Alkyne‐Tethered Oximes and Alkenes

“…[12] As shown in entry 1, the desired product (3aa) could be delivered in 84 %yield in the presence of 10 mol % of Fe(acac) 3 as the catalyst and 2equivalents of PhCO 2 Na after stirring in 1,4-dioxane at 80 8 8Cfor 12 h. Thestructure of 3aa was unambiguously confirmed by single-crystal X-ray diffraction. [13] By replacing Fe(acac) 3 with FeCl 3 ,F eCl 2 , Fe(OTf) 2 ,o rF e(OAc) 2 ,t he reaction occurred albeit with lower yields (entries 2-5). Thei ron salt is crucial for this transformation, because no desired product was observed in the absence of the iron catalyst (entry 6).…”

“…As shown in Tables 3a nd 4, cinnamonitrile 2k and crotononitrile 2o displayed different regioselectivity in the transformations.I no rder to understand such ar egioselectivity,t hese two alkenes were calculated at the same level (Scheme 8). [24] Fort he cinnamonitrile 2k,t he energy barrier for the formation of intermediate M was lower than that of intermediate L,because the phenyl group could stabilize the transition state E2-ts.I nt he case of crotononitrile 2o,t he cyano group could stabilize for transition state E3-ts,w hich would lead to the formation of more favorable intermediate O.…”

“…Note that, the aryl group of the cinnamo-nitrile was introduced into the ortho position of the pyridine Natom, which was unambiguously confirmed by singlecrystal X-ray diffraction. [14] Such as ubstructure would be useful, since the aryl group might be further modified by Ndirecting-group-assisted C À Hb ond functionalization. [15] With the reaction conditions shown in Table 2[(Fe(acac) 3 , PhCO 2 Na, 80 8 8C],t he substrate scope of both oximes and alkenes remains relatively narrow.T oa pply this method to ab roader range of substrates,s uch as acrylonitrile and crotononitrile,w es lightly modified the reaction conditions, and pleasingly found that the combination of FeCl 2 and PivONa was applicable for more oximes and alkenes (Table 4).…”

“…[23] Furthermore,u nder the conditions similar to those shown in Table 2, 1a could be transformed into am ultisubstituted cyclopentene compound 12 in the absence of the alkene (Scheme 5c). [24] Theg eneration of such ac ompound might involve the interception of av inyl radical with the benzoate (Scheme 6).…”

Synthesis of Poly‐Substituted Pyridines via Noble‐Metal‐Free Cycloaddition of Ketones and Imines

“…[6] Among the various cycloaddition reactions to pyridines, the formal [4 + 2] cycloaddition approach with α,βunsaturated imine derivatives as the "four-atom" units represented one of the most straightforward ones (Scheme 1). [7][8][9][10][11][12][13][14][15][16][17][18] Liu and Liebeskind reported the synthesis of substituted pyridines through a cascade reaction comprising a coppercatalyzed N-iminoalkenylation of α,β-unsaturated ketoximes with alkenylboronic acids, an electrocyclization, and an oxidative aromatization. [8] Cheng and co-workers realized an elegant formal [4 + 2] reaction of α,β-unsaturated ketoximes with internal alkynes through a rhodium-catalyzed chelation-assisted CÀ H activation, offering a one-pot synthesis of poly-substituted pyridine derivatives.…”