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Subtitle: Light-induced LMCT process of Cu(II) carboxylates, achieving decarboxylation cross-coupling of carboxylic acids
Carboxylic acids and their derivatives have the advantages of cheap and easy to obtain, rich in variety and stable properties, so decarboxyl coupling reactions using them as raw materials have become a powerful tool for constructing complex structures and diverse active molecules. Currently, the most common modern decarboxylation coupling strategy is inherently redox-neutral, i.e., cross-coupling of carboxylic acid nucleophils to electrophils (Figure 1a) and is widely used in the C-C bond construction of electrophilic organic halides. In contrast, the construction of polar C-N and C-O bonds often requires the use of internal oxidants (e.g., hydroxyphthalimide (PINO), iodinyl esters) to pre-functionalize the carboxylic acid (Figure 1b), resulting in cumbersome reaction steps and complex product purification. On the other hand, Net-oxidative decarboxylation cross-coupling not only avoids the need for pre-functional grouping, but also provides a direct strategy for installing simple nitrogen and oxygen nucleophiles, the most classic of which is the electro-deconypellation kolbe reaction, but the process requires a solvent amount of heteronuclear reagent as a sacrificial oxidant and there is a competing Kolbe dimerization. In addition, many research groups have also reported on the synthesis of electrocatalytic decarboxyl ethers, electrocatalytic Ritter reactions and high temperature-promoted transition metal-mediated oxidative decarboxylation couplings, but the above strategies still have problems such as poor functional group tolerance, pre-functional grouping, poor chemical selectivity, and chemical doses of oxidants, which seriously hinder the development of decarboxylation cross-coupling reactions.
Figure 1. Common strategies for decarboxyl conjugation reactions. Image credit: Nat. Chem.
In 2020, Larionov's group reported a metal photoredox strategy that successfully achieved decarboxylation coupling of a variety of carboxylic acids and aromatic amines (Angew. Chem. Int. Ed., 2020, 59, 7921–7927）。 On this basis, the research group of Professor Tehshik P. Yoon of the University of Wisconsin-Madison in the United States envisages whether the intrinsic photochemical properties of Cu(II) salts can be used to achieve decarboxyl coupling reactions through the light-induced ligand-metal charge transfer (LMCT) process. Recently, they have achieved copper-mediated oxidative decarboxylation coupling reaction with a variety of nucleophilic reagents under visible light exposure (Figure 1c). Preliminary mechanism studies have shown that the chromophores in this reaction are in situ assembled Cu(II) carboxylate species, and that the visible light-induced ligand-metal charge transfer (LMCT) process can lead to free radical decarboxylation, triggering oxidative cross-coupling. The results were published in Nature Chemistry.
Figure 2. Screening of reaction conditions. Image credit: Nat. Chem.
Given the important pharmaceutical activity of sulfonamide compounds in medicinal chemistry, the authors selected 1-phenylpropionic acid (1a) and 4-methoxybenzenesulfonamide (1b) as model substrates to screen for the reaction conditions for decarboxyl coupling (Figure 2). First, when irradiated with a 427 nm LED lamp in the presence of alkali and Cu(OTf)2, only trace amounts of products (Entry 1) were observed in several common organic solvents; the single and double tooth ligands commonly found in Cu-mediated transformation did not promote the occurrence of reactions (Entry 2, 3), while acetonitrile as a ligand could improve reaction yield (Entry 4). It should be noted that this reaction is extremely sensitive to acetonitrile, with the best reaction effect at 5.0 equiv, while a higher dosage will generate a Ritter adduct3. Further studies of the structure of the nitrile ligand showed that the nitrile ligand i-PrCN (5.5 equiv) responded best (Entry 7-11), yielding products at a 73% yield2. In addition, control experiments show that the reaction must have light conditions (Entry 12). Finally, when the authors reacted with an unrefined solvent in an atmospheric environment, they obtained product 2 (Entry 13) at a yield of 58%, reflecting the simple operability of the coupling reaction.
Figure 3. Screening of reaction conditions. Image credit: Nat. Chem.
Under optimal conditions, the authors investigated substrate compatibility for decarboxyl coupling reactions (Figure 3). For arylacetic acid substrates, the aromatic hydrocarbons substituted to the electron group have the best effect (9-13), in particular the orthomethyl group (14), α- branched chain (18-22) substituted substrate and even α - amino acids (24) can be compatible with the reaction, with a moderate to better yield to obtain the desired product. Unfortunately, unsaturated aliphatic carboxylic acids do not participate in this reaction (28), which preferentially undergo oxidative elimination rather than nucleophilic substitution reactions, but stereoscopically limited amantane carboxylic acids can perform the reaction smoothly (25, yield: 69%). On the other hand, the substrate range of the coupling reagent sulfonamide is also wider, whether it is a deficient / electron sulfonamide substrate (2, 5-8) or heteroaryl (15, 34) and alkyl (19, 30, 31) substituted primary sulfonamide or even secondary sulfonamide (23) can achieve this conversion, with a good yield to obtain cross-coupling products. In addition, the reaction can also tolerate a variety of functional groups, such as: aryl halides (7, 11-14, 34), ester groups (16), carbamates (24), sulfamates (26), acetals (27), polycyclic aromatic hydrocarbons (26, 27) and the like. Finally, the authors found that the reaction was also well reactive and functionally tolerant to the later modifications of the new drug candidate (29-34), further highlighting the strength of the reaction.
After the successful realization of the decarboxylation cross-coupling reaction between carboxylic acid and sulfonamide, the authors explored the reactivity of different types of nucleophilic reagents (Figure 4). Specifically, reducing the ratio of nucleophiles to 1.5 equivalents and reacting in MeCN allows a series of carbamates (35-38) and amide (39) nucleophiles to be successfully coupled. In addition, Ritter amidation (40-46) can be achieved by decarboxylation in a nitrile solvent without the need for external nucleophils, providing an attractive alternative to Curtius rearrangement of aryl acetic acid. In addition, alcohols are not easily coupled as nucleophiles. To this end, the authors further optimized the reaction conditions, with toluene as the solvent, MeCN as the ligand, and pyridine as the alkaline additive can significantly improve the reaction performance, so as to smoothly obtain the decarboxylation etheration product (47-71), while also having good functional group tolerance, such as: terminal olefins (64, 66), heterocyclic (63, 69, 70), protected sugars (70), sulfonamides (69), haloalkanes (67) and alkynes (68). Most notably, this strategy is not only limited to the construction of carbon-heterobonds, but is equally applicable to the formation of carbon-carbon bonds, e.g., heteroaryl hydrocarbons (72-74) and electron-rich aromatics (75) can obtain decarboxyl Frieder-Crafts alkylation products with good yields.
Figure 4. Cross-coupling reaction substrate expansion of different nucleophiles. Image credit: Nat. Chem.
Finally, the authors speculate on the reaction mechanism. As shown in Figure 5a, carboxylic acids and Cu (OTf)2 are assembled in situ under the basis of alkali-mediated to form photoactive chromophores Cu(II) carboxylates, which undergo an LMCT process under photoexcitation to generate carboxyl radicals that are easy to deacidify, followed by carboxyl radical decarboxylation to produce alkyl radicals. Subsequently, the alkyl radicals are oxidized by Cu(II) to carbocations, and nucleophilic substitution occurs to obtain the final product. To further confirm the hypothetical reaction mechanism, the authors designed the following experiments: 1) primary carboxylic acid 32a was given a 5-exo-trig cyclization product of a decarboxyl radical intermediate under Ritter amidation conditions (FIG. 4b); while cyclopropyl-substituted acetic acid 33a was obtained under ether oxide condition 77 (Fig. 5c). These results provide key evidence for the involvement of carbon-centric radical intermediates; 2) UV-visible titration experiments have shown that monomer species corresponding to low energy absorption characteristics are responsible for decarboxylation coupling reactions, which is very consistent with empirically optimized reaction conditions (Figure 5d). The addition of a low concentration of 1a- will observe a longer absorption band of λmax = 304 nm, which is comparable to the LMCT band of other monomer Cu(II) carboxylate complexes reported in the literature. If the concentration of 1a- is greater than 1 equivalent, Cu(II) causes the above features to disappear and there is an increase in the higher energy band of λmax = 260 nm, which is comparable here to the LMCT absorption band of the paddle wheel Cu(II) carboxylate dimer; 3) with the increase of the concentration of 1a, the reaction yield decreases rapidly, with the unreacted 1a accounting for the majority, and leading to dimer blueshift. When irradiated with a 254 nm light source (close to the λmax of the high-energy feature) 1a and 1b, only trace amounts of 2 and benzyl radical dimerization products 78 (Figure 5e) are formed, while the 427 nm light source does not react. Based on the above results, although free radicals can be produced in a variety of Cu(II) carboxylate species, oxidation and subsequent nucleophilic coupling occur only in lower-energy visible light-activated complexes.
Figure 5. Reaction mechanism study. Image credit: Nat. Chem.
summary
Professor Tehshik P. Yoon's research group has developed a copper-catalyzed carboxylic acid oxidative cross-coupling strategy with various nitrogen, oxygen and carbon nucleophiles. The system utilizes the inherent photochemical reaction characteristics of the first transition metal coordination complex generated in situ and can be photoactivated without the addition of a precious metal photoredox catalyst. The reaction system is not only suitable for a variety of carboxylate feedstocks and nucleophiles, but also provides a powerful tool for the synthesis and post-modification of complex structural drug candidates.
Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu (II) carboxylates
Qi Yukki Li, Samuel N. Gockel, Grace A. Lutovsky, Kimberly S. DeGlopper, Neil J. Baldwin, Mark W. Bundesmann, Joseph W. Tucker, Scott W. Bagley, Tehshik P. Yoon
Nat. Chem., 2022, 14, 94–99, DOI: 10.1038/s41557-021-00834-8
Instructor introduction
Tehshik P. Yoon
https://www.x-mol.com/university/faculty/108
(This article is contributed by pyridoxal)