Metalloradical approach for concurrent control in intermolecular radical allylic C-H amination

Abstract

Although they offer great potentials, the high reactivity and diverse pathways of radical chemistry pose difficult problems for applications in organic synthesis. In addition to the differentiation of multiple competing pathways, the control of various selectivities in radical reactions presents both formidable challenges and great opportunities. To regulate chemoselectivity and regioselectivity, as well as diastereoselectivity and enantioselectivity, calls for the formulation of conceptually new approaches and fundamentally different governing principles. Here we show that Co(II)-based metalloradical catalysis enables the radical chemoselective intermolecular amination of allylic C-H bonds through the employment of modularly designed D₂-symmetric chiral amidoporphyrins with a tunable pocket-like environment as the supporting ligand. The reaction exhibits a remarkable convergence of regioselectivity, diastereoselectivity and enantioselectivity in a single catalytic operation. In addition to demonstrating the unique opportunities of metalloradical catalysis in controlling homolytic radical reactions, the Co(II)-catalysed convergent C-H amination offers a route to synthesize valuable chiral α-tertiary amines directly from an isomeric mixture of alkenes.

Fig. 1 |. Radical pathways for direct functionalization of allylic C–H bonds: challenges, opportunities and solution.

a, Organic free radical pathway involving HAA and XAA. This classic HAA–XAA pathway for allylic radical C–H functionalization faces the longstanding challenge to control multiple selectivities associated with both steps, which typically generate an isomeric mixture of products. b, Metallorganic radical pathway HAA–RS. This proposed HAA–RS pathway, which is based on the introduction of α-metallorganic radicals L_nM–X^· to replace free organic radicals, may offer a potential solution to address the challenging issue of multiselectivities, and possibly form the product as a single enantiomer.

Fig. 2 |. Convergent radical amination of allylic C–H bonds with organic azides via Co(II)-based MRC.

a, Targeted catalytic reaction for allylic C–H amination of trisubstituted alkenes 2 with organic azides 1 to produce chiral α-tertiary allylic amines 3. The proposed mechanism consists of an initial metalloradical activation of azide 1 by a Co(II) metalloradical catalyst to generate α-Co(III)-aminyl radical I, subsequent HAA from the allylic C–H bonds of alkene 2 by radical intermediate I and final RS of the Co(III)–amido complex ^bII by allylic radical ^aII in the resulting ∞-Co(III)-alkyl radical II. b, Proposed concurrent convergence of multiselectivities. The proposed mechanism via a Co(II)-based MRC could offer an opportunity to achieve allylic C–H amination by directly employing a mixture of allylic isomers, such as constitutional, (E)/(Z) and enantiomeric isomers, as starting materials as they would all converge to the same allylic radical intermediate ^aII after HAA. Por, porphyrin.

Fig. 3 |. Mechanistic studies on the Co(II)-based metalloradical system for convergent amination of allylic C–H bonds.

a, Measurement of the KIE. The high degree of the competitive primary KIE is consistent with the proposed step of C–H bond cleavage via intermolecular HAA by the α-Co(III)-aminyl radical intermediate I. b, Trapping of the allylic radical intermediate by TEMPO. The observation of TEMPO-trapped product 6a provides evidence for the existence of the ∞-Co(III)-allylic radical intermediate II from HAA of the allylic C–H bond by the initially generated α-Co(III)-aminyl radical intermediate I during the catalytic process. c, DFT study of the ligand effect on the regioselectivity of Co(II)-catalysed allylic C–H amination. Top: difference in energy barriers (ΔΔG^‡) for RS at the two allylic radical sites by [Co(P1)]. Bottom: difference in energy barriers (ΔΔG^‡) for RS at the two allylic radical sites by [Co(P2)]. The NCI plot clearly indicates multiple NCIs, such as two-point hydrogen-bonding interactions and π–π stackings that exist in the TS. DFT calculations (all values in kcal mol⁻¹) were performed at the SMD(Benzene)-BP86-D3(BJ)/def2TZVP//BP86-D3(BJ)/def2SVP level of theory. r.t., room temperature.

Fig. 4 |. Synthetic applications of the resulting chiral α-tertiary amines from Co(II)-catalysed allylic C–H amination.

a, Stereoselective conversion of the enantioenriched α-tertiary amino acid ester (E)-3aa to epoxide-containing amino acid ester 7 by epoxidation with meta-chloroperoxybenzoic acid (mCPBA); to amino alcohol (E)-8 by reduction with DIBAL-H; this could be further converted into chiral alcohol 10 by hydrogenation on Pd/C and to trisubstituted furan 11 by bromoetherification, followed by double elimination and subsequent bromination; to fully reduced amino alcohol 9 by reduction with dihydrogen on Pd/C and followed with DIBAL-H, which could be further converted into benzomorpholine 12 by intramolecular nucleophilic substitution and to aziridine 13 by treatment with MsCl followed by intramolecular nucleophilic substitution; to (Z)-3aa by photocatalytic isomerization. b, Stereoselective conversion of α-tertiary amino acid ester (E)-3ia to give unprotected α-tertiary amino acid ester (E)-15 by oxidation with CAN via the p-quinonimide intermediate (E)-14 and to N-heterocycle (E)-16 by oxidation with CAN followed by reaction with n-butylamine.