Carbene is a highly active intermediate with two unbonded electrons on a carbon atom that can participate in a variety of reactions, such as insertion reactions, cyclopropylation reactions, rearrangement reactions, etc. Carbenes or carbenoid-like intermediates are easy to use, but building them can be challenging. At present, methods for the construction of carbene intermediates mainly rely on highly active, difunctional or pseudo-difunctional precursors (e.g., diazo (or pro-diazo) compounds, polyhalides, or thioleafrider, etc.), nucleophilic attack on the metal center to form metal-carbene complexes, followed by heterocleavage α-elimination (depending on the appropriate metal oxidation state) to form a second metal-carbon bond. However, the high activity and structural specificity of these starting materials limit their application and in some cases present safety concerns (e.g., the need for high temperatures and/or explosive reagents). Although Motherwell and Nagib et al. have demonstrated that carbonyl intermediates can be used as carbenes from pregenerated zinc carbenees, there is still a lack of a general strategy to obtain carbenes from other naturally occurring and abundant starting materials such as carboxylic acids, amino acids, and alcohols.
In order to address the long-standing limitations of carbene chemistry, the research group of Professor David W. C. MacMillan of Princeton University in the United States (click to view the introduction) used metal photoredox strategies to perform radical addition and reduction-induced α-elimination processes on six different types of non-traditional leaving groups, and then successfully converted commercially available chemical raw materials into iron carbene species (Fig. 1a). The specific process is as follows, the free radical precursor forms a free radical under the action of visible light, and then the first metal-carbon bond is produced by free metal-based metalization, followed by the single-electron reduction of the metal center to initiate α-elimination to release the departing group and obtain the desired metal-carbene species. In addition, this method can perform cyclopropaneation and N-H, S-H, and P-H bond insertion reactions from abundant and stable carboxylic acids, amino acids, and alcohols, thus providing a versatile solution to carbene-mediated chemical diversification challenges while avoiding many of the shortcomings of traditional carbene synthesis strategies. The results were published in Nature.
Figure 1. Reaction design. Image source: Nature
First, the authors selected α-acetoxycarboxylic acid as the radical precursor, iron porphyrins as the metal backbone to evaluate the radical bonding and α-elimination, and the cyclopropanation reaction as the model reaction to capture the putative carbene intermediate α. The cyclopropaneation reaction was successfully achieved by blue light irradiation under the conditions of 5,10,15,20-tetras(4-methoxyphenyl)-21H,23H-porphyl ferric chloride (Fe(TMPP)Cl) and Ir(dFCF3ppy)2dttbpyPF6 as catalysts, and the required cyclopropaneation products could be obtained with 95% yield after optimizing the reaction conditions. In addition, control experiments showed that all reaction components were critical, with no product formation in the absence of iron catalyst, light, or Hantzsch esters, while yields were reduced to 36% in the absence of iridium photocatalysts, consistent with the Hantzsch ester-mediated electron-donor-acceptor complexes for radical generation. Second, the authors explored the leaving groups of other radical precursors, and the results showed that NHPI esters of a series of lactic acid derivatives substituted by non-traditional α-oxidative leaving groups (e.g., α-phenoxy, α-methoxy, and α-hydroxy) were compatible with this reaction (Fig. 1b), yielding the corresponding cyclopropaneation products at 77-95% yields. In addition to this, the authors also evaluated the potential of α-amino acids as free radical precursors, and the results showed that the toluenesulfonyl and trifluoromethanesulfonyl-protected α-amino acids obtained the desired cyclopropane products in good yields, although most of the protecting groups were ineffective. Taken together, the authors identified six different leaving groups that could act as carbene precursors, demonstrated the tolerance of iron porphyrins α-elimination to various leaving groups (> 10 pKa units), and provided a modular strategy for obtaining carbene intermediates.
Figure 2. Substrate Expansion One. Image source: Nature
Under optimal conditions, the authors explored the substrate range of carboxylic acids and olefins (Figure 2). The results showed that both benzyl and alkyl carbenes produced from α-acetoxycarboxylic acid were effective coupling partners, and could smoothly perform cyclopropaneation reactions with styrene (1) and electron-rich olefins (2-4), which was consistent with the electrophilic reactivity of iron porphyrin carbene intermediates proposed by the authors. In addition, benzyl carbamate (CBz)-protected dehydroalanine (5) and complex backbone derivatives with various functional groups (6-8), α-methoxy (9-14) and α-phenoxy(15) carboxylic acid substrates, α-amino acid precursors (e.g., tosyl-protected alanine (16), methionine sulfoxide (17), leucine (18), and lysine (19)) and even α-bromoacetate precursors (20-26) can be converted to the corresponding cyclopropaneation products in moderate to good yields, where the tertiary amine substrate (7) is protonated with 1 equiv trifluoromethanesulfonic acid for cyclopropaneation reaction, because the tertiary amine will undergo competitive oxidative side effects under photoredox conditions in the traditional method.
Figure 3. Substrate expansion II. Image source: Nature
On the other hand, fluoromethylated cyclopropane has become a valuable building block in medicinal chemistry due to its unique physicochemical properties and biological activity, but fluoromethylated cyclopropane is often synthesized by diazo species. Recently, chemists have discovered that N-hydroxyphthalimide-activated β-fluoroalcohols can be cleaved by the 1,2-hydrogen atom transfer (HAT) process to generate ketyl radical intermediates, so the authors attempted to construct fluoroalkylated cyclopropane products with alcohol-derived ketyl intermediates as effective precursors. As shown in Figure 3, the cyclopropylation of styrene derivatives was successfully achieved using the inexpensive and readily available 2,2,2-trifluoroethyl-NHPI ether as a free radical precursor using a metal photoredox strategy, especially the unprotected indole (29), carboxylic acid (30), free amine (31), aniline and Cbz-protective amine (35-37) could also tolerate this reaction, thus demonstrating the compatibility of the strategy for acidic and basic functional groups. Second, electron-deficient styrene (32), diene (33), uracil-derived enamide (34), vinyl benzoate (38) containing α-ester groups can also be converted to the corresponding trifluoromethylated cyclopropane products in moderate to good yields, where enamide 34 reacts only at electron-rich olefins, which is consistent with the electrophilic ferroporphyrin carbene reactivity. Notably, this conversion can also be achieved with 2,2-difluoroethanol as the starting material, resulting in the desired difluoromethyl-substituted cyclopropane product in moderate yields (47-51).
Figure 4. σ-key insertion reaction. Image source: Nature
Finally, the authors used the properties of iron carbine to investigate other σ-bond insertion reactions (Figure 4), specifically: 1) β-fluoroalcohols and carboxylic acid derivatives successfully achieved P-H bond insertion reactions (52 and 53); 2) S-H bond insertion reaction between mercaptan and β-fluorohydrin and carboxylic acid derivatives was carried out to successfully synthesize (difluoro)alkylated thioether products (54 and 55); 3) N-H bond insertion reaction between β-fluoroalcohols and carboxylic acid derivatives with aniline and amines, respectively, to obtain N-alkylated products in good yields (56-59); 4) Aniline obtains a monoalkylated amine product (60, yield: 64%) by reacting with NHPI-activated α-phenoxypropionic acid, thereby bypassing the conventional reactivity of amide bond formation. In summary, the successful demonstration of σ-bond insertion in the above different environments further reveals the ability of carbine intermediates to participate in the formation of useful bonds outside of cyclization and establishes their ability as reactive intermediates.
summary
Prof. MacMillan's group has successfully converted commercially available chemical raw materials into iron carbene species by radical addition and reduction-induced α-elimination of six different types of unconventional leaving groups using a metal photoredox strategy. This method allows for cyclopropanation and N-H, S-H, and P-H bond insertion reactions from abundant and stable carboxylic acids, amino acids, and alcohols, thus providing a versatile solution to carbenene-mediated chemical diversification challenges while circumventing many of the drawbacks of traditional carbene synthesis strategies.
Unlocking carbene reactivity by metallaphotoredox α-elimination
Benjamin T. Boyle, Nathan W. Dow, Christopher B. Kelly, Marian C. Bryan, David W. C. MacMillan
Nature, 2024, DOI: 10.1038/s41586-024-07628-1
Instructor introduction
David W. C. MacMillan
https://www.x-mol.com/university/faculty/156328
(This article was contributed by pyridoxal)