Iron(III)-based metalloradical catalysis for asymmetric cyclopropanation via a stepwise radical mechanism

Abstract

Metalloradical catalysis (MRC) exploits the metal-centred radicals present in open-shell metal complexes as one-electron catalysts for the generation of metal-stabilized organic radicals-key intermediates that control subsequent one-electron homolytic reactions. Cobalt(II) complexes of porphyrins, as stable 15e-metalloradicals with a well-defined low-spin d⁷ configuration, have dominated the ongoing development of MRC. Here, to broaden MRC beyond the use of Co(II)-based metalloradical catalysts, we describe systematic studies that establish the operation of Fe(III)-based MRC and demonstrate an initial application for asymmetric radical transformations. Specifically, we report that five-coordinate iron(III) complexes of porphyrins with an axial ligand, which represent another family of stable 15e-metalloradicals with a d⁵ configuration, are potent metalloradical catalysts for olefin cyclopropanation with different classes of diazo compounds via a stepwise radical mechanism. This work lays a foundation and mechanistic blueprint for future exploration of Fe(III)-based MRC towards the discovery of diverse stereoselective radical reactions.

Fig. 1 |. Proposed stepwise radical mechanism for cyclopropanation of alkenes with in situ-generated α-trifluoromethyldiazomethane via Fe(III)-based metalloradical catalysis.

a, Co(II)-based metalloradical catalysis has emerged as a general catalytic approach for controlling the reactivity and selectivity of homolytic radical reactions. As stable 15e-metalloradicals, cobalt(II) complexes of porphyrins have been demonstrated with the capability of activating diazo compounds to generate α-Co(III)-alkyl radicals that can function as kinetically competent intermediates for catalytic carbene transfer reactions through a stepwise radical pathway. b, Iron(III) complexes of porphyrins have not been unambiguously established as genuine catalysts for catalytic transformations. They have been commonly assumed to be in situ-reduced to Fe(II) complexes as the actual catalysts for catalytic carbene transfer reactions through a concerted ionic pathway via metallocarbene intermediates. c, As another family of stable 15e-metalloradicals, Fe(III) complexes of porphyrins might have the potential to function as one-electron catalysts to homolytically activate diazo compounds such as in situ-generated α-trifluoromethyldiazomethane 1′ for catalytic radical cyclopropanation of alkenes 2 to form trifluoromethyl-substituted cyclopropanes 3. During this proposed Fe(III)-based metalloradical catalysis, the initially generated α-Fe(IV)-alkyl radical intermediates I could undergo radical addition to alkenes 2 to form γ-Fe(IV)-alkyl radicals II that would subsequently proceed via intramolecular radical substitution to deliver the cyclopropane products 3 while regenerating the Fe(III)-metalloradical catalysts.

Fig. 2 |. Comparative studies on catalytic cyclopropanation and detection of intermediates by HRMS to probe the oxidation state of iron porphyrin catalysts.

a, To probe the oxidation state of the active iron catalyst, comparative studies on catalytic cyclopropanation of alkenes 2 with in situ-generated α-trifluoromethyldiazomethane (1′) by [Fe(P3)Cl] were performed under a nitrogen atmosphere and in air, as well as in the absence and presence of DMAP. As a parallel comparison, the catalytic cyclopropanation reaction was also carried out with the [Co(P3)] as the catalyst in the absence and presence of DMAP. b, HRMS-ESI detection of α-Fe(IV)-alkyl radical I_{[Fe(p3)Cl]/4b} from a reaction mixture of ethyl diazoacetate (4b) and [Fe(P3)Cl]. c, HRMS-ESI detection of α-Fe(IV)-alkyl radical I_{[Fe(P3)Cl]/4l} from a reaction mixture of α-phenyldiazomethane (4l′) and [Fe(P3)Cl].

Fig. 3 |. DFT calculations on the catalytic mechanism for olefin cyclopropanation by [Fe(P3)CI].

a, DFT calculations on the catalytic pathway and associated energies for the asymmetric cyclopropanation of styrene with α-trifluoromethyldiazomethane (1′) by [Fe(P3)Cl] in three different spin states. b, DFT study on the origin of the enantioselectivity of the asymmetric cyclopropanation of styrene with α-trifluoromethyldiazomethane (1′) by [Fe(P3)Cl].

Fig. 4 |. Determination of iron spin states in [Fe(Por)Cl].

a, Measurement of the magnetic moment of [Fe(P3)Cl] by variable-temperature SQUID and Evans methods. b, X-band EPR measurement for [Fe(P3)Cl] at different temperatures.

Fig. 5 |. Experimental studies on the catalytic mechanism of olefin cyclopropanation by the Fe(III)-based metalloradical system.

a, Trapping of the α-Fe(IV)-alkyl radical intermediate by spin traps PBN and DMPO for EPR detection. b, Trapping of α-Fe(IV)-benzyl radicals from metalloradical activation of aryldiazomethanes by Ph₃SiH and by TEMPO. c, Probing of the γ-Fe(IV)-alkyl radical intermediate by cyclopropanation reactions of (E)- and (Z)-β-deutero-p-methoxystyrene. d, Dependence of the cyclopropanation reaction rate on concentrations of substrates and catalyst through kinetic studies.