Unlocking carbene reactivity by metallaphotoredox α-elimination

Abstract

The ability to tame high-energy intermediates is important for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often unknown, high-energy intermediates^1,2. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the carbon-metal bond. However, these methods are usually prohibitive because of reagent safety concerns, limiting their broad implementation in synthesis^3-6. Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to metal to forge the initial carbon-metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Here we realize this strategy through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N-H, S-H and P-H bonds from abundant and bench-stable carboxylic acids, amino acids and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.

Extended Data Fig. 1 |. Proposed mechanism for iron porphyrin carbene formation through metallaphotoredox catalysis.

Metallaphotoredox-mediated formation of iron porphyrin carbene intermediates exploiting a single-electron reduction mediated α-elimination. Me, methyl; Et, ethyl, Ac, acetyl; Phth, phthalimide; HEH^•+, oxidized Hantzsch ester; Ir, Ir(dFCF₃ppy)₂dttbpy; Fe, iron porphyrin. For further commentary and discussion see Fig. S1.

Fig 1 |. Enabling carbene reactivity via odd-electron intermediates

a. Radical starting materials as alternatives to hazardous and limiting traditional carbene precursors. b. General approach to iron carbene reactivity through carboxylic acids, amino acids, and alcohol precursors using metallaphotoredox for cyclopropanation and σ-bond insertion. Me, methyl; Boc, tert-butyloxycarbonyl; Et, ethyl; Bz, benzoyl; Nphth, phthalimide; Ac, acetyl; Tf, trifluoromethylsulfonyl; Ts, 4-toluenesulfonyl; Ph, phenyl. LG corresponds to α-elimination leaving group and varies based on radical precursor utilized.

Fig 2 |. Scope of photoredox-enabled iron carbene cyclopropanation using carboxylic acids as precursors.

α-Acetoxy, α-methoxy, α-phenoxy carboxylic acids, α-amino acids, and α-bromo acetates can be used as carbene precursors. Experiments run with 1.0 equiv. of olefin, 2.0 equiv. carbene precursor, 3.0 equiv. Hantzsch ester or 3.5 equiv. AdNHSi(TMS)₃, 5 mol% iron catalyst, and 2 mol% Ir photocatalyst irradiating using a Penn Integrated Photoreactor with 450 nm plates for 12 hours. For amine containing substrates, 1.0 equiv. trifluoromethanesulfonic acid (TfOH) was added to the reaction prior to irradiation. Isolated yields shown except where noted. Major diastereomer shown (d.r. reported from crude reaction mixtures and is relative stereochemistry around cyclopropane). *¹H NMR yield using 1,3,5-trimethoxybenzene as an internal standard. See Supplementary Information for experimental details. LG, leaving group; HE, Hantzsch ester; Si·, AdNHSi(TMS)₃; Boc, tert-butyloxycarbonyl; Bn, benzyl; Et, ethyl; Ph, phenyl; Me, methyl; Cbz, benzyl oxycarbonyl; NPhth, phthalimide; Ts, 4-toluenesulfonyl; Ac, acetyl; tBu, tert-butyl, iPr, isopropyl.

Fig 3 |. Scope of tri- and difluoromethyl cyclopropanation through carbene metallaphotoredox.

Formal 1,2-HAT ketyl radical generation for carbene reactivity from β-fluoro alcohols. Experiments run with 1.0 equiv. of olefin, 2.0 equiv. carbene precursor, 3.0 equiv. Hantzsch ester, 5 mol% iron catalyst, and 2 mol% Ir photocatalyst irradiating using a Penn Integrated Photoreactor with 450 nm plates for 12 hours. For amine containing substrates, 1.0 equiv. trifluoromethanesulfonic acid (TfOH) was added to the reaction prior to irradiation. Isolated yields shown except where noted. Major diastereomer shown (d.r. reported from crude reaction mixtures and is relative stereochemistry around cyclopropane). See Supplementary Information for experimental details. *¹⁹F NMR yield using 4-fluoro methylbenzoate as an internal standard. Boc, tert-butyloxycarbonyl; Bn, benzyl; Et, ethyl; Ph, phenyl; Me, methyl; Cbz, benzyl oxycarbonyl; NPhth, phthalimide; Ac, acetyl; Bz, benzoyl; nProp, normal propyl; tBu; tert-butyl, iPr, isopropyl.

Fig. 4 |. σ-bond insertions through metallaphotoredox carbene formation.

P–H, S–H, and N–H insertion is viable using carboxylic acid and alcohol derived precursors through iron carbene intermediates. Experiments run with 1.0 equiv. of olefin, 2.0 equiv. carbene precursor, 3.0 equiv. Hantzsch ester, 5 mol% iron catalyst, and 2 mol% Ir photocatalyst irradiating using a Penn Integrated Photoreactor with 450 nm plates for 12 hours. Isolated yields shown. See Supplementary Information for experimental details. Ph, phenyl; Me, methyl; NPhth, phthalimide.