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Synlett 2023; 34(12): 1327-1342
DOI: 10.1055/a-2012-5317
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Special Issue Honoring Masahiro Murakami’s Contributions to Science

Recent Advances on the Carboxylations of C(sp3)–H Bonds Using CO2 as the Carbon Source

Suman Pradhan
,
Shoubhik Das  ∗

S.D. acknowledges financial assistance from the Odysseusprogramme and Fonds Wetenschappelijk Onderzoek (FWO) (Research Foundation – Flanders).
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Dedicated to Prof. Masahiro Murakami for his unparalleled contributions on the topic of CO2 utilization in organic synthesis.

Abstract

Carbon dioxide (CO2) is widely known as being a sustainable C1 synthon for the synthesis of various carboxylic acid derivatives, including essential natural and unnatural amino acids. While it is sustainable, the high thermodynamic stability and kinetic inertness of the CO2 molecule is a major drawback to its wider use in organic synthesis. However, the reduction of this inert and highly stable CO2 molecule has been carried out successfully over the past few years using various stoichiometric as well as catalytic approaches. Initially, chemists employed transition-metal/transition-metal-free thermochemical methods for the incorporation of CO2 into organic compounds, however, gradually, the introduction of greener approaches such as visible-light-induced photoredox catalysis and electrocatalysis became revolutionary for the synthesis of carboxylic acids under mild reaction conditions. In this short review, we discuss the recent advances in carboxylation reactions via functionalization of the (sp3)C–H bonds of various organic molecules with CO2 using thermochemical, photochemical and electrochemical methods.

1 Introduction

2 Transition-Metal/Transition-Metal-Free Thermochemical Carbox ylations of C(sp3)–H Bonds

2.1 C(sp3)–H Bond Carboxylation of Carbonyls

2.2 Allylic, Benzylic and Alkyl C(sp3)–H Bond Carboxylation

3 Photochemical C(sp3)–H Bond Carboxylation

3.1 Allylic C(sp3)–H Bond Carboxylation

3.2 Benzylic C(sp3)–H Bond Carboxylation

4 Electrochemical Carboxylation of C(sp3)–H Bonds

5 Conclusion and Outlook


#

Key words

carbon dioxide - transition-metal - transition-metal-free - thermochemical strategy - visible-light-induced photocatalysis - electrocatalysis - reductive C–H carboxylations - carboxylic acids

Biographical Sketches

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Suman Pradhan received his master’s degree from Ramakrishna Mission Residential College, Narendrapur, University of Calcutta in 2016. He then joined the research group of Dr. Indranil Chatterjee in November 2017 at the Indian Institute of Technology, Ropar, India as a Ph.D. student. After finishing his Ph.D. in September 2022, he joined the group of Prof. Shoubhik Das at the University of Antwerp, Belgium as a postdoctoral fellow. Currently, he is working on C–H bond carboxylation reactions.

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Shoubhik Das received his Ph.D. under the supervision of Prof. Matthias Beller at the Leibniz-Institut für Katalyse in 2012. Subsequently, he joined the research group of Prof. Matthew Gaunt at Cambridge University as a postdoctoral research associate. In 2013, he moved to the research group of Prof. Paul J. Dyson at the EPFL, Switzerland. In August 2015, he started his independent research career at Georg-August-Universität Göttingen. In November 2019, he joined the Department of Chemistry at the University of Antwerp. His main research interests are the activation of small molecules and their applications in organic synthesis and fuel generation.

1

Introduction

The carboxylic acid unit is omnipresent in bioactive drug molecules, pharmaceuticals, natural products, and agrochemicals.[1] Various synthetic protocols have been established for the straightforward synthesis of carboxylic acids via the oxidation of alcohols, aldehydes, and hydrocarbons, the hydrolysis of nitriles, and through carbonylation strategies.[2] However, these methods have serious drawbacks such as low functional group tolerance, poor step economy, and are associated with toxic reagents such as carbon monoxide.[2] In this direction, for the construction of one of the most fundamental linkages, i.e., C–C bonds (to synthesize carboxylic acids), the employment of CO2 has expanded hugely over the past few decades due to its unique reactivities. In general, CO2 has several positive aspects, such as its high abundance in our environment, its non-toxicity, and its low-cost. Owing to these important characteristics, CO2 has been identified as a superior C1 synthon and has become an ideal feedstock for the synthesis of carboxylic acids via the construction of C–C bonds.[3] [4] [5] However, using CO2 as a reagent is a challenging task due to its high thermodynamic stability and kinetic inertness.[6] Having sluggish reactivity, harsh reaction conditions, such as high temperatures and pressure, are often required when CO2 is used as a substrate. However, these drawbacks have not distracted from the wide possibilities for the utilization of CO2 in organic synthesis. For example, fixation of CO2 was formerly carried out by using stoichiometric organometallic reagents, which often necessitated the use of harsh reaction conditions. Additionally, several catalytic methods, such as (transition)-metal-free protocols and transition-metal-catalysis,[3b] [e] [5b] [7] have emerged for the utilization of CO2 in the past few decades.

In the search for green and sustainable techniques in organic synthesis, visible-light-mediated photoredox catalysis has come into the forefront.[8] This approach has the remarkable ability to conduct particular transformations that were previously unattainable by other strategies. Photoredox catalysis is efficiently able to replace various toxic and harsh reaction conditions, where stoichiometric metal reductants were used for the terminal reduction, by merging visible light with suitable photocatalysts. Parallel to photoredox catalysis, modern organic synthesis has also witnessed an enormous surge in the use of electrocatalysis.[9] This environmentally benign strategy is considered important for the future of organic synthesis since it can be employed to replace several synthetic strategies where extra additives or metal reactants are utilized to carry out a transformation.

Organic molecules such as hydrocarbons, drug molecules and polymers contain diverse C–H bonds.[10] The functionalization of these bonds certainly carries high value in the synthetic chemistry arena due to their broad application in syntheses of natural products, pharmaceuticals, and organic materials. The direct C–H bond functionalization technique represents a new field of research compared to conventional organic synthesis, where much attention is paid towards selective transformation of a functional group. The advantages of this direct strategy are that (a) it can be applied for selective C–H bond functionalization, even in the presence of more reactive functional groups,[10a] [11] (b) the ready availability of starting materials and no requirement for prefunctionalization(s), and (c) it generally produces less waste as by-products.

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Scheme 1 General carboxylation strategies via the functionalization of C–H bonds using CO2

Consequently, reacting two ubiquitous reaction partners such as C–H-bond-containing organic molecules and CO2 will provide easier access to high value-added carboxylic acid derivatives in a single step and maintaining high sustainability.[12] While the carboxylation reactions of sp and sp2 C–H bonds have been widely developed, the exploration of sp3 C–H bonds is progressing slowly.[3r] [13] However, the wide prevalence of C(sp3)–H bonds in natural products and pharmaceuticals, has forced scientists to explore this arena. In previous studies, transition-metal or transition-metal-free methodologies proceeded through C(sp3)–H bond carboxylation reactions via enolate chemistry to trap a CO2 molecule in order to give carboxylation products.[7] [14] However, these thermochemical protocols suffer from harsh reaction conditions, metal toxicity, and (over)stoichiometric amounts of bases. To avoid all these drawbacks, visible-light-mediated photoredox catalysis[3o] [15] and electrocatalysis[16] have been widely used for the carboxylation of C(sp3)–H bonds using CO2, where a single-electron transfer (SET) approach is followed to achieve the final products. Currently, two possible pathways are involved using photo/electrochemical carboxylation of C–H bonds with CO2: (a) the use of CO2 as a mild electrophile,[6a] and (b) the use of CO2 as a nucleophile, i.e., the generation of [CO2]•– after single-electron reduction.[17] Generally, a reduced anionic (carbanion or other) species is often required to capture the electrophilic CO2 for carboxylation, whereas nucleophilic [CO2]•– usually undergoes a radical addition or a radical–radical coupling reaction to form the new C–C bond. Therefore, it is quite evident that these newly developed approaches will have a lasting impact in academia and industry by providing alternative reaction routes.[9] Over the past few years, several reviews have been published on the utilization of CO2 in carboxylation reactions by using transition-metal catalysis,[7] photocatalysis,[3o] [15] and electrocatalysis.[16] Nevertheless, this is the first review that discusses various challenges and possibilities for C(sp3)–H bond carboxylation reactions in which CO2 is directly used as a substrate in thermochemical, photochemical and electrochemical reaction pathways (Scheme [1]).


# 2

Transition-Metal/Transition-Metal-Free Thermochemical Carboxylations of C(sp3)–H Bonds

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Scheme 2 Silver-catalyzed carboxylations via the functionalization of C(sp3)–H bonds in carbonyl compounds

Prior to the development of photoredox and electrocatalysis, Lewis acid, metal or metal-free thermochemical approaches were widely used for the carboxylation of C–H bonds to achieve carboxylic acids.[7] Several reports on transition-metal-catalyzed aromatic C–H bond carboxylation, heterocyclic olefinic and alkyne C–H bond carboxylation are well documented in the literature.[14] However, selective catalytic carboxylation of C(sp3)–H bonds by fixing CO2 gas is a daunting task in current organic chemistry due to the lack of reactivity and kinetic inertness of both reaction partners. In this short review we describe only C(sp3)–H bond carboxylation techniques.

2.1

C(sp3)–H Bond Carboxylation of Carbonyls

Carboxy-functionalization of the α-C–H bonds of carbonyls remains an important transformation due to the importance of the synthesized products, β-ketocarboxylic acids, which are crucial intermediates towards pharmaceutically active molecules.[18] However, due to the thermodynamic instability and inclination towards decarboxylation, the synthesis of β-ketocarboxylic acids is normally avoided.[3r] [13] Therefore, in situ transformation of β-ketocarboxylic acids into other stable entities, such as cyclic esters, was carried out previously.[19]

In pursuit of this, Yamada’s group described a silver-catalyzed carboxylative cyclization reaction of alkynyl-substituted ketones 1 (Scheme [2a]).[20] During an evaluation of the substrate scope of this protocol, both electron-rich and electron-poor substrates responded well under the developed reaction conditions. However, neutral and electron-deficient substrates required longer reaction times for conversion into the respective products. Mechanistically, the conversion progresses via the generation of an enolate from the alkynyl-ketones upon treatment with a base. The formed enolate readily reacted with CO2 and generated the β-ketocarboxylate intermediate 3. Here the silver catalyst activated the C≡C bond to guide the lactone formation via intramolecular capture of the β-ketocarboxylate into the alkyne system. During the course of the reaction, exclusive site selectivity was observed by the authors, as was evident from the sole formation of γ-lactones 2, despite the presence of two different protons (α and α′) adjacent to the carbonyl group. The Z geometry of the C=C bond in the lactone product was confirmed by characterizing the molecule by single-crystal X-ray diffraction and by 2D NMR (NOE) experiments. Dihydrofuran derivatives were detected as side products, albeit in lower yields (ca. 5%). Delightfully, the scope of the reaction was extended by the successful application of aliphatic carbonyls.

In 2013, the same group developed another silver-catalyzed carboxylative cyclization reaction of o-alkynyl acetophenones 4 (Scheme [2b]).[21] The combination of a silver acetate catalyst and an organic base, 1,8-diazabicyclo(5.4.0)-7-undecene (DBU), selectively afforded isobenzofuranylidene acetic acid derivatives 5 in good yields (47–99%). Regardless of the electronics, substrates possessing electron-donating or electron-withdrawing groups favored the formation of the desired products in high yields (up to 97%). A terminal-alkene-containing o-alkynyl acetophenone was also transformed into the desired product 5d, albeit in a low yield of 47%. Similarly, here also silver activated the tethered C≡C bond to initiate the intramolecular 5-exo-dig regioselective cyclization and deliver the dihydroisobenzofuran compounds 5, bearing an aromatic substituent at the alkynyl-moiety, with exclusive Z selectivity with respect to the C=C bonds. This strategy is highly appealing due to the facile access to dihydroisobenzofuran derivatives, the core structural unit of various biologically active molecules such as pestacin and escitalopram.

In 2014, Zhang et al. documented a similar reaction strategy for the carboxylative cyclization of o-alkynyl acetophenones 7 to furnish dihydroisobenzofuran derivatives 8 (Scheme [2c]).[22] The authors used AgBF4 as the catalyst and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) as an organic base to obtain isobenzofuranylidene acetic acid derivatives in 50–93% yields. Various substituted aryl/alkyl alkynylacetophenones were well tolerated and afforded the corresponding single isomeric products in excellent yields (up to 93%). In this report, detailed mechanistic investigations were achieved by conducting DFT calculations and deuterium-labelling experiments. After performing detailed DFT calculations, the authors did not observe any energy barrier when the oxygen atom approached the carbon center in 5-exo fashion cyclization, which explains the reason behind the exclusive 5-exo oxygen cyclization reaction. After conducting the deuterium labelling experiment, the source of the α-proton in the synthesized product was found to the α-methyl group of the acetophenone derivative 7 (these methyl protons are indicated in Scheme [2c])

In 2017, Yamada and co-workers further extended their previously reported carboxylative cyclization reaction methodology, and demonstrated the silver-catalyzed carboxylation of conjugated ynones 9 with CO2 to afford highly functionalized tetronic acid frameworks 10 (Scheme [2d]).[23] Here also, electronically poor substrates showed slightly sluggish reactivity which had an impact on the yield (e.g., 10b, 62%). The authors also applied these reaction conditions for the synthesis of aspulvinone E (10c) in three steps, which was previously obtained in six steps.[24]

Parallel to the α-C(sp3)–H carboxylation of alkyne-containing carbonyls, carboxylation via functionalization of the γ-C(sp3)–H bond of alkene-containing carbonyls also provided valuable products. However, only a few reports have been documented for the γ-carboxylation of carbonyl γ-C(sp3)–H bonds. Apart from Yoshida’s report on the ethylzinc carbamate assisted carboxylative cyclization of 4-methyl-3-penten-2-one with CO2,[25] no reports were documented until 2016. However, this strategy had some drawbacks as it required an (over)stoichiometric amount of an organic base (Et3N or pyridine) at high temperature (160 °C).

In 2016, Zhang and co-workers filled this much awaited gap by reporting a transition-metal-free carboxylative cyclization of propenyl ketones 11 with CO2 to produce the highly important α-pyrone structural motif via γ-carboxylation reactions (Scheme [3]).[26] In fact, the presence of lactone and diene functionalities in the pyrone molecule enhances the importance of the protocol as the pyrone can be widely used as a synthetic intermediate in cycloaddition and ring-opening reactions.[27] The designed methodology was widely utilized for the synthesis of α-pyrones from a variety of β-alkylchalcones. Indole-containing substrate 11f also provided the corresponding pyrone 12f in 45% yield. An essential-oil-derived naturally occurring organic compound pulegone was carboxylated (12g) efficiently under the reported reaction conditions. Initially, the propenyl ketone was deprotonated by the base to provide enolate intermediate 13a, which upon reaction with CO2 furnished the keto-ester species 13b. Finally, base-promoted cyclization of the keto-ester delivered the desired α-pyrone products 12.

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Scheme 3 Base-mediated carboxylation via functionalization of the C(sp3)–H bonds in carbonyl compounds

# 2.2

Allylic, Benzylic and Alkyl C(sp3)–H Bond Carboxylation

Strategies behind the synthesis of complex and versatile organic molecules have guided the functionalization of native C–H bonds (such as allylic and alkyl C(sp3)–H bonds) immensely. Even though the bond energy of a C(sp3)–H bond is quite high, the functionalization of these bonds has been vigorously practiced for the construction of high-value C–C-bond-containing molecular frameworks.

In 2012, Sato, Mita and Michigami reported a transition-metal-catalyzed nitrogen-directing-group-assisted selective formal benzylic C(sp3)–H bond activation/silylation, followed by a selective carboxylation reaction with CO2 assisted by cesium fluoride (Scheme [4]).[28] In this report, the authors utilized a unique set of reaction conditions in which only the benzylic C(sp3)–Si bond was carboxylated, while keeping the aromatic C(sp2)–Si bond intact. The reaction followed two steps: (a) [{Ir(cod)Cl}2]- or [Ru3(CO)12]-catalyzed silylation of the benzylic C(sp3)–H bond and aromatic C(sp2)–Si bond, and (b) fluoride-mediated selective carboxylation of the benzylic C(sp3)–Si bond. The Ir catalytic system was efficiently applied for the selective carboxylation of 8-methylquinoline derivatives. Besides this, several 2-substituted pyridines were well tolerated when the Ru catalyst was utilized. Initially, the substrate was silylated with Et3SiH in the presence of the Ir or Ru catalyst, and after that, the benzylic silylated intermediate 16 was readily carboxylated in the presence of CO2 by the treatment with CsF.

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Scheme 4 Transition-metal-catalyzed carboxylation via functionalization of the C(sp3)–H bond in substituted toluenes

Later, in 2013, the same group made extended their previous findings and elaborated the substrate scope.[29] They found that silylation of the benzylic C(sp3)–H bond adjacent to a nitrogen-directing group (pyridine, isoquinoline, quinoline, etc.), could be achieved by using [Ir(cod)OMe]2 or [{Rh(cod)Cl}2] as the catalyst. Subsequent treatment with a fluoride source yielded the α-amino acid derivative by cleaving the benzylic C(sp3)–Si bond.

In 2017, Sato and Mita’s research group reported another method for the carboxylation of allylic C(sp3)–H bonds of terminal alkenes 17 with CO2 (Scheme [5a]).[30] This transformation was carried out by using a Co-catalyst and Xantphos as the ligand. The catalytic Co/Xantphos complex transformed a diverse array of allyl arenes and 1,4-dienes into linear styryl acetic acid and hexa-3,5-dienoic acid frameworks, respectively, in good yields (up to 84% yield). In the presence of other carbonyl compounds (ketone, ester and amide), selective addition of CO2 occurred at the C(sp3)–H site by employing the optimized reaction conditions. Gratifyingly, neutral, electron-rich and electron-poor allylic arenes responded positively during the synthesis of linear carboxylic acids. Furthermore, heteroarene-containing allyl arenes and 1,4-dienes gave the desired products (i.e., 18c, 63% 18e, 78%) regioselectively in good yields. However, this protocol was not efficiently applied in the case of a simple terminal alkene as a mixture of regioisomers was formed in low yield (18d + 18d′ + 18d′′ = 24%), which certainly will prompt further studies on the carboxylation of less reactive terminal alkenes in the future. In their communication, the authors strategically selected one of the synthesized compounds, 18f, to synthesize optically active γ-butyrolactone 19 in two steps via a Sharpless asymmetric dihydroxylation. The γ-arylbutyrolactone derivative 19 was used for the preparation of the useful tricyclic pharmacophore 20 by utilizing previously reported reaction conditions.[31]

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Scheme 5 Transition-metal-catalyzed carboxylation via the functionalization of allylic C(sp3)–H bonds

Mechanistically (Scheme [5a]), the authors proposed the involvement of different oxidation states of Co in the Co-catalyst (CoI, CoII and CoIII), and according to the authors, a low valent CoI-methyl species was generated from the reaction of the cobalt salt, the Xantphos ligand and AlMe3. This CoI-methyl species followed concomitant steps (coordination of the substrate, reductive elimination of methane, electrophilic attack by CO2 at the γ-position of the low valent allyl-Co complex VIII) to produce the desired carboxylated products. In this conversion, CsF played a crucial role in increasing the yield of the product, possibly by interacting with CO2 and facilitating its solvation in the reaction medium.

At the same time, Hou’s group demonstrated a copper-catalyzed direct allylic C(sp3)–H bond carboxylation of allyl aryl ethers with CO2 to furnish 2-aryloxy-3-butenoates in good to excellent yields (54–91%) (Scheme [5b]).[32] Irrespective of the substituents on the aromatic ring, various aryl arenes were successfully tolerated. An α-methylallyl diisopropylcarbamate derivative underwent carboxylation at the more sterically hindered site to give 22d in 89% yield. Unfortunately, alkyl allyl ethers were found to be incompatible under the optimized reaction conditions. Mechanistically, upon adding the base ( i Bu3Al(TMP)Li), alumination at the C(sp3)–H site was observed via selective deprotonation of the phenyl allyl ethers. The formed allylaluminum species underwent a Cu-NHC-complex-catalyzed carboxylation reaction with CO2. Electron-donating and electron-withdrawing substituents on the aryl ring did not affect the reaction and the desired 3-butenoates were obtained with high regio- and stereoselectively.

Alkyl halides are commonly used as one of the electrophilic coupling partners in classical cross-coupling reactions.[33] In such reactions, we usually experienced the formation of a new bond at the prefunctionalized site. However, forming a new bond away from the prefunctionalized position is a challenging task. To solve this issue, in 2017, Martin’s group reported a nickel-catalyzed carboxylation of remote unfunctionalized C(sp3)–H bonds of non-activated aliphatic hydrocarbons (mainly alkanes or crude olefin mixtures, 23) with admirable regio- and chemoselectivity (Scheme [6]).[34] In this work, the authors were able to strategically switch the site-selectivity and guide the carboxylation reaction to occur at the less-reactive distant terminal sites in the presence of more reactive prefunctionalized sites. The authors applied the optimal reaction conditions to various secondary and tertiary alkyl bromides to obtain C(sp3)–H-bond-carboxylated products in excellent yields (up to 86%). The reaction was highly chemoselective since reactive functional groups such as hydroxy, ketone, ester, sulfonamide, acetal, and nitrile did not interfere during this transformation. As this was a base-free process, a substrate with acidic protons was also tolerated, affording product 25d in 50% yield. To highlight the wide applicability of their methodology, they also used raw materials that were directly obtained from petroleum processing. Pleasingly, when a multiple C(sp3)–H-bond-containing isomeric mixture of olefins (26/27/28 = 1:1:1 that required no separation) was employed under the standard reaction conditions, a single carboxylic acid product 29 (terminal carboxylation) was obtained regioconvergently. Similarly, pure α-olefin 30 was selectively carboxylated to give acid 31, which is a primitive component for the synthesis of nylon.

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Scheme 6 Nickel-catalyzed carboxylation via functionalization of C(sp3)–H bond in alkanes

In this reaction paradigm, the β-hydride elimination process was nicely controlled by the appropriate choice of ligands on the Ni catalyst. This proper management of ligands accelerated the β-hydride elimination step from the Ni(I)-alkyl species in advance of CO2 insertion. Subsequently, a Ni-chain-walking process via iterative β-hydride elimination/migratory insertion sequences provided Ni(I)-alkyl intermediates (V and VI). Thereafter, the reductant (Mn) assisted CO2 to insert into the catalytic cycle to afford the carboxylic acid derivatives 25 and complete the catalytic cycle by regenerating the Ni(0) species (I) (Scheme [6]).


#
# 3

Photochemical C(sp3)–H Bond Carboxylation

To functionalize inert, non-activated C–H bonds, the free-radical process is mainly followed in classical organic synthesis. In these processes the site-selectivity is monitored either by intramolecular hydrogen atom abstraction or by the relative strengths of the C–H bonds.[35] Another possible way to functionalize these bonds is via prefunctionalization at the desired site, which results in an increase of reaction steps and reduces atom economy. Visible-light photocatalysis has come into the organic synthesis arena as a blessing and applies unique reactivity patterns to overcome the challenges associated with the functionalization of the C(sp3)–H bonds. The process of visible-light photocatalysis usually follows SET (single-electron transfer) and photoinduced HAT (hydrogen atom transfer) pathways to install diverse functional groups. Among these functionalizations, carboxylations are a highly intriguing topic of investigation. Additionally, photocatalytic processes have several positive aspects: (a) a greener approach (uses light energy), (b) the photocatalyst will activate a non-reactive bond selectively by SET or energy transfer, and (c) the reactions mostly occur at room temperature.

3.1

Allylic C(sp3)–H Bond Carboxylation

Direct functionalization of allylic C(sp3)–H bonds is always cherished due to the formation of densely functionalized complex alkene-containing molecules. As these bonds are not so reactive in nature, harsh reaction conditions and stoichiometric metal reagents are often employed for such functionalization. In 2016, Murakami’s research group developed an elegant methodology of dual-copper-organocatalytic allylic C(sp3)–H bond carboxylation with CO2 under irradiation with UV light (Scheme [7]).[36]

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Scheme 7 UV-light-induced, ketone-catalyzed carboxylation via the functionalization of allylic C(sp3)–H bonds

During these investigations, cyclic as well as acyclic alkenes were investigated.[36] Notably, when a naturally occurring monoterpene (β-pinene) was applied, the corresponding carboxylated product was obtained, albeit with a lower turnover number (TON = 1.3). However, this methodology suffered from selectivity issues, such as when two different allylic C–H bonds were present in the same molecule, with mixtures of isomers being isolated. For the mechanism, the authors proposed the formation of highly reactive homoallyl alcohol intermediate (IV) upon reaction between excited ketone photocatalyst (II) and alkene 32. The homoallyl alcohol species then entered the copper catalytic cycle and underwent an allylic transfer reaction (between the homoallylic alcohol and CO2) to afford the carboxylic acid derivative 33 with an excellent TON.


# 3.2

Benzylic C(sp3)–H Bond Carboxylation

Similar to allylic C(sp3)–H bonds, benzylic C(sp3)–H bonds also required special attention in order to enable their functionalization. Murakami et al. pioneered the direct carboxylation of non-activated C(sp3)–H bonds with CO2 using light energy sources. In 2015, his group came up with an intriguing idea for the direct benzylic C(sp3)–H bond carboxylation reaction under irradiation with UV light (Scheme [8]).[37] In this method, CO2 was used as the carboxylating reagent and the transformation occurred in the absence of any catalyst. Several substituted o-alkylphenyl ketones bearing halo, acetal, OMe, OH, and CHO groups on the aromatic ring were successfully converted into their carboxylic analogues in good to excellent yields (up to 95%). Interestingly, selective mono-carboxylation (36b) was achieved in 95% yield when a bis(o-tolyl) ketone was employed. One of the synthesized products, 36e, was used for the preparation of 2,3-benzodiazepine 37, an anxiolytic and sedative drug molecule.

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Scheme 8 UV-light-induced catalyst-free carboxylation via the functionalization of benzylic C(sp3)–H bonds

Mechanistically, upon UV irradiation, the ketone substrate 35 was excited and enolized to form the diradical species (II), which then readily yielded o-quinodimethane intermediate (III). Species (III) underwent a [4+2] cycloaddition reaction with CO2 and then further reacted to provide the carboxylic acid derivative 36 (Scheme [8]).[37] It should be mentioned that this work featured the first [4+2] cycloaddition reaction of CO2 to harness carboxylic acids 36 via functionalization of the C(sp3)–H bond.

Later, in 2017, Jamison and co-workers developed an efficient technology for carboxylation of the benzylic C–H bonds of benzyl amine derivatives 38 using the organic photocatalyst p-terphenyl (42) (Scheme [9]).[38] They were able to conduct the single-electron reduction of CO2 to [CO2]•– (IV) via oxidative quenching of the photocatalyst. It is noteworthy to mention that the reduction potential of CO2 appears to be quite high (E0 = –2.21 V vs SCE in DMF), which is beyond the capability of most photocatalysts. Upon using p-terphenyl as the photocatalyst, the generation of [CO2]•– species (IV) excelled, which propagated the transformations to their conclusions. Parallel to the batch reactions, the authors also performed continuous-flow reactions to yield α-amino acid derivatives. In the continuous-flow method, the yield of the product (92%) and the rate of the transformation (10 min) were found to be very high. In contrast, in the batch reaction, a lower yield (30%) was obtained, even after conducting the reaction for 2 hours with constant purging of CO2. Various amines containing aromatic substituents (alkyl, halogen) and even free N–H bond (39b) bearing substrates were tolerated well to yield the corresponding products. Apart from cyclic amino acids, several cyclic heteroarene-containing amino acids (39c,f) and acyclic amino acids (39d) were synthesized efficiently. However, electron-poor amines remained unreactive under these reaction conditions.

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Scheme 9 UV-light-induced organic-photocatalyzed carboxylation via functionalization of C(sp3)–H bonds in benzyl amines

Mechanistically, reductive quenching of the photocatalyst (PC) was carried out by SET from the amine to generate amine radical-cation species (I). This radical-cation intermediate then underwent deprotonation to produce the carbon-centered radical (II). On the other hand, the reduced photocatalyst readily reduced CO2 to provide [CO2]•– species (IV). The radical–radical cross-coupling between (II) and (IV) furnished the corresponding α-amino acid in good to excellent yield (up to 87%) (Scheme [9]).[38] However, the use of an over-stoichiometric quantity of potassium trifluoroacetate resulted in an increase of reaction waste.

In 2019, the group of Murakami reported an innovative protocol of light-induced CO2 fixation into benzylic C–H bonds, utilizing an aromatic ketone as a photosensitizer as well as a HAT catalyst. This was followed by applying a Ni catalyst for the subsequent coupling reaction (Scheme [10]).[39]

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Scheme 10 UV-light-induced dual-Ni/organocatalyzed carboxylation via functionalization of a benzylic C(sp3)–H bond

Despite the success with benzylic C–H bonds, this unique method was also operative on non-activated C–H bonds, such as in linear aliphatic and cycloalkanes, to achieve the corresponding carboxylic acids. The reported strategy displayed better selectivity for secondary C–H bonds compared to the stronger primary C–H bonds.[39] This site-selective reaction methodology was successfully applied to various electron-rich aromatics to afford mono-carboxylated products (e.g., 44b) exclusively in the presence of other similarly reactive benzylic C–H bonds. A highly important drug molecule, homoveratric acid (44c) (a human xenobiotic and urinary metabolite), was synthesized in 81% yield following the reported reaction steps. Unfortunately, electron-poor arenes afforded carboxylic acids either in lower yields (e.g., 44d) or no conversion was observed (e.g., 3-benzoyl- and 4-cyanotoluenes). Delightfully, the authors also showed the robustness of this methodology by performing the carboxylation of saturated aliphatic hydrocarbons such as cyclopentane (45) and n-pentane (47). However, a mixture of regioisomers was obtained from n-pentane (47) in a 1:8:3 (48/49/50) ratio.

Distinct from König’s mechanistic proposal,[40] this transformation was accelerated by the trapping of benzylic alkyl radicals (V) by Ni(0), which triggered the formation of the alkyl-Ni(I) intermediate (VII) for the facile CO2 insertion to finally deliver carboxylic acids 44 (Scheme [10]). Furthermore, the ketone radical-anion species (IV) reduced the Ni(I) intermediate to generate Ni(0) for catalytic turnover via a SET process. It is worth mentioning that the presence of a substituent (e.g., methyl) at the benzylic position hampered the reactivity, presumably due to the higher stability of the secondary benzylic radical and its steric hindrance towards radical addition to the Ni(0) center.

At a similar time, König and co-workers came up with an improved reaction strategy (metal, ligand and base-free) to perform benzylic C(sp3)–H bond carboxylation reactions under irradiation with visible light (Scheme [11]).[40] In this work, the authors overcame the previous limitations (such as the use of a transition-metal catalyst, a base and high energy UV light) and were able to carboxylate the secondary benzylic C(sp3)–H bond more efficiently to yield the 2-arylpropionic acid derivatives 52. An organic photocatalyst, 4-CzIPN (2,4,5,6-tetrakis(9H-carbazol-9-yl)isophthalonitrile), and a HAT reagent, i Pr3SiSH, were used to carry out this transformation. In this report, the authors investigated a series of aliphatic and aromatic thiol-containing HAT reagents, wherein HAT 1 (Scheme [11]) was found to be the best. Substituents at various positions of the aromatic ring, irrespective of electronics, provided very good yields (up to 89%) of the corresponding products. However, substrates containing Br or I substituents and aldehydes and ketones were not responsive under their developed reaction conditions. In addition to the mechanistic features, the key feature of this proposed protocol was the synthesis of the bioactive molecules fenoprofen, flurbiprofen and naproxen. Mechanistically, the authors proposed that the formation of an active photocatalyst, 4-CzPEBN (2,3,4,6-tetra(9H-carbazol-9-yl)-5-(1-phenylethyl)benzonitrile) (53) (formed upon reacting the organic dye 4CzIPN with ethylbenzene), was the critical part of this transformation. Thereafter, 4-CzPEBN (53) acted as the main active photosensitizer and a typical dual-organo/photoredox catalytic cycle was depicted for the C(sp3)–H bond carboxylation with CO2 (Scheme [11]). According to the authors, kinetic isotope effect studies suggested that the breaking of C–H bonds was the rate-determining step.

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Scheme 11 Visible-light-induced dual organo-photocatalyzed carboxylation via functionalization of benzylic C(sp3)–H bonds

There are limitations such as metal-catalyzed ipso-CO2 insertions at the prefunctionalized site associated with the remote sp3 C–H carboxylation.[34] [41] To address these limitations, Martin and König introduced a carboxylation technique with CO2, using alkyl halides as precursors, at the remote and non-activated sp3 C–H sites, which was aided by merging visible-light-mediated dual-photoredox catalysis (Scheme [12]).[42] In this method, they successfully functionalized benzylic and primary sp3 C–H bonds and anticipated the reactivity. The non-innocent role of water was confirmed when a lower yield (50%) was obtained after using desiccants to remove water. Both electron-rich (Me, OMe, OH) and electron-poor (aldehyde, ester) benzylic substrates responded well under their optimized reaction conditions, with substrates bearing electron-donating groups providing the best results. During investigations with non-activated alkanes, the standard reaction conditions were successfully applied over several functional groups, such as nitriles, esters, amides, ketones, and alkyl chlorides. The site-selectivity was controlled by modification of the ligand backbone. By utilizing the reported reaction conditions, non-activated n-heptane (57) was also readily carboxylated with high terminal regioselectivity (99:1).

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Scheme 12 Visible-light-induced dual-Ni/organocatalyzed carboxylation via the functionalization of C(sp3)–H bonds; HE = Hantzsch ester; l = linear; b = branched

Mechanistically, a photoredox Ni-catalyzed chain-walking carboxylation at the sp3 C–H site was proposed. According to DFT calculations: (a) intermediates (III) and (V) had similar energy, (b) facile β-H elimination occurred from the cationic Ni(II) species, (c) CO2 insertion on Ni(II) species (V) was unfavorable, and (d) either an outer- or inner-sphere mechanism triggered the formation of a Ni(I)-carboxylate by incorporating CO2 at the Ni(I) center in (VI), which was generated upon SET. However, the authors were unable to provide any experimental explanation for the definite involvement of Ni(I) and Ni(II) intermediates during the chain-walking step (Scheme [12]).[42]

In the previous report by Martin and König,[42] the methodology suffered from the over-stoichiometric use of the reductant, the Hantzsch ester (HE) and the Ni-organophotoredox-mediated dual-catalytic systems for the benzylic and remote sp3 C–H bond carboxylation with CO2. In 2020, Yu and co-workers reported a Ir-photoredox catalytic system for remote sp3 C–H bond carboxylation via alkene difunctionalization reactions whilst avoiding the use of a reductant (Scheme [13]).[43]

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Scheme 13 Visible-light-induced Ir-photoredox-catalyzed carboxylation via the functionalization of C(sp3)–H bonds

Under such reaction conditions, the benzylic C(sp3)–H bond was efficiently carboxylated with CO2. Various substituents (esters, amides, carbonates, halides, alkynes) on the central phenyl ring of the benzylic amides provided the corresponding products in moderate to good yields (44–78%). Delightfully, a geminal-disubstituted alkene afforded the difunctionalized product 61f in 59% yield. Mechanistically, the non-activated pendant alkene was first difunctionalized upon reaction with the Langlois reagent (CF3SO2Na) (a CF3 radical precursor) (Scheme [13]). The generated carbon-centered radical then underwent a 1,5-HAT process to provide a benzylic carbon-centered radical, which after oxidative quenching of the photocatalyst afforded the benzylic carbanion species (IV). Finally, interaction of electrophilic CO2 with species (IV) yielded the corresponding carboxylic acid.


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# 4

Electrochemical Carboxylation of C(sp3)–H Bonds

In the pursuit of achieving mild and environmentally benign reaction conditions beyond vastly explored thermochemical and photoredox catalysis, the invention and conceptualization of electrocatalysis entered the arena of organic synthetic chemistry.[16] Indeed electrocatalysis displays several advantages such as (a) no requirement of a sacrificial electron donor, (b) the use of free electrons as the reductant, and (c) mild reaction conditions. A typical electrocatalytic process usually follows cathodic reduction, anodic oxidation and finally, combines the reduced and the oxidized species to achieve the final product. In comparison to thermochemical and photochemical carboxylation methods, several points can be raised. Firstly, in the case of thermo/photochemical processes the use of a transition-metal catalyst or additives are usually required, whereas electrocatalytic transformations can follow a transition-metal-free pathway. Secondly, in the majority of cases, external oxidants or reductants are not required for electrocatalytic processes. Thirdly, electrocatalytic processes are ideal for global sustainability as renewable energy sources are often utilized to carry out reactions. In contrast, a high reaction temperature is often essential for conducting a particular transformation via a thermochemical pathway. Hence, there is no doubt that electrocatalysis can play an imperative role in carboxylation reactions. Similar to photoredox chemistry, this method also follows the SET pathway for the carboxylation. Mechanistically, a typical electrocatalytic carboxylation reaction occurs via (a) cathodic SET reduction of the substrate and successive addition to electrophilic CO2, and (b) cathodic SET reduction of CO2 to generate a nucleophilic [CO2]•– species that reacts with the electrophilic substrate. It should be mentioned that so far electrocarboxylation has been mainly explored for the carboxylation of olefins and imines, and only a few reports have been published on direct electrocatalytic C(sp3)–H bond carboxylation reactions.[16]

In 2006, the first report on C(sp3)–H bond carboxylation with CO2 appeared from the Senboku group (Scheme [14]).[44] The authors strategically carboxylated the α-C–H bond of carbonyl compounds 63 to give the corresponding β-keto carboxylic acids 64 using the anode as the sacrificial reductant. Various cyclic as well as acyclic ketones were investigated successfully under the optimized reaction conditions, where acyclic ketones provided lower yields of products (64c,d; 30–34%). Unsymmetrical ketone 63e provided regioselective carboxylated products 64e and 64e′ in a 9:1 mixture (terminal vs branched). In this reaction, the oxidation and reduction were conducted at the Mg anode and the Pt cathode, and tetrabutylammonium hexafluorophosphate was used as the supporting electrolyte. From a mechanistic rationale, the cathodic reduction of CO2 took place. The generated [CO2]•– species (I), which proved to be the crucial intermediate in this transformation, performed the deprotonation of carbonyl substrates 63 to form the enolate intermediate (II). The combination of enolate (II) and CO2 then led to the desired products in moderate to good yields (up to 92%) (Scheme [14]).

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Scheme 14 Electrochemical carboxylation via functionalization of the α-C(sp3)–H bond in carbonyl compounds

In 2019, Kim, De Vos and Mechez revealed that the benzylic C–H bond of the benzyl alcohol 65 could be carboxylated with CO2 using electrochemical reaction conditions (Scheme [15]).[45] They used glassy carbon (GC) as the non-sacrificial anode and Ni as the cathode in the presence of tetraethylammonium chloride (TEAAc) as the electrolyte. TEMPO was used as the mediator, which oxidized the aromatic alcohol to afford the aromatic ketone 67 at the GC anode. The aromatic ketone was then reduced at the cathode (nickel) and finally the radical-anion species (I) coupled with CO2 to furnish the benzoic acid derivative 66.

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Scheme 15 Electrochemical carboxylation via functionalization of the benzylic C(sp3)–H bond in a benzyl alcohol

# 5

Conclusion and Outlook

In conclusion, this short review highlights a wide range of methods for the carboxylation of various organic feedstocks with CO2 using metal or metal-free thermochemical methods, visible-light photocatalysis and electrocatalysis. We have only focused on carboxylations proceeding via functionalization of the C(sp3)–H bonds of alkanes, alcohols, amines, and carbonyl-containing compounds for the synthesis of the corresponding carboxylic acid derivatives. The importance of the synthesized carboxylic acids in chemical and pharmaceutical industries has also triggered high interest in this research field. Several novel techniques (catalytic or stoichiometric) have emerged in recent decades, which have revealed novel reactivities for the controlled incorporation of CO2 into organic compounds. Among these techniques, visible-light-induced photocatalysis and electrocatalysis have been widely explored recently due to their notable applications as viable and green energy sources. Despite the flourish in carboxylation reactions, various other transformations of lactones, lactams and heterocyclic compounds have also gained significant attention, thus broadening the area of CO2 utilization in organic synthesis. One of the future prospects for C(sp3)–H bond carboxylation is the enantioselective synthesis of carboxylic acid derivatives via the induction of chirality. Recently, synthetic chemists around the globe have started to explore the asymmetric insertion of CO2 into C(sp3)–H bonds.[46] We believe that the utilization of CO2 for the carboxylation of organic compounds will expand further in future due to its ability to produce highly important molecular scaffolds whilst simultaneously maintaining global sustainability.

Despite such commendable outcomes, there are plenty of complications and obstacles that need to be addressed beforehand. In order to use these reported methodologies for practical applications, improvements in the reaction strategies are highly desirable and existing limitations have to be overcome. These limitations are: (a) the mechanistic rationale of various additive-mediated transformations is hypothesized, and has not been fully investigated experimentally. (b) Several (sp3)C–H bond carboxylation reactions require noble metals (e.g., Ag, Ir, Ru) as catalysts or stoichiometric reagents (these noble metals often contribute to toxic traces of metals in the synthesized products) and generate unwanted metal by-products. Thus, the replacement of these highly toxic expensive transition metals with more abundant and economically favorable 3d metals (Fe, Mn, Cu or Co) should be the upcoming target for scientists. (c) The carboxylation of kinetically inert, non-activated remote (sp3)C–H bonds has been not fully explored yet (only a few nickel-catalyzed methodologies have been demonstrated). (d) The electrochemical reduction of CO2 for the carboxylation of (sp3)C–H bonds still lags far behind and more attention is required to further develop this environmentally benign methodology.

The chemistry of CO2 fixation is captivating and is rapidly becoming a highly thriving topic of interest due to the importance of the synthesized carboxylic acid derivatives. Gratifyingly, several other possibilities such as photocatalytic, electrocatalytic, flow-reaction methodology and AI (artificial intelligence)-based strategies can be foreseen for the efficient sequestration of CO2 into useful carboxylated products.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Shoubhik Das
Department of Chemistry, University of Antwerp
2020, Antwerp
Belgium   

Publication History

Received: 15 December 2022

Accepted after revision: 13 January 2023

Accepted Manuscript online:
13 January 2023

Article published online:
16 February 2023

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Scheme 1 General carboxylation strategies via the functionalization of C–H bonds using CO2
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Scheme 2 Silver-catalyzed carboxylations via the functionalization of C(sp3)–H bonds in carbonyl compounds
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Scheme 3 Base-mediated carboxylation via functionalization of the C(sp3)–H bonds in carbonyl compounds
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Scheme 4 Transition-metal-catalyzed carboxylation via functionalization of the C(sp3)–H bond in substituted toluenes
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Scheme 5 Transition-metal-catalyzed carboxylation via the functionalization of allylic C(sp3)–H bonds
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Scheme 6 Nickel-catalyzed carboxylation via functionalization of C(sp3)–H bond in alkanes
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Scheme 7 UV-light-induced, ketone-catalyzed carboxylation via the functionalization of allylic C(sp3)–H bonds
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Scheme 8 UV-light-induced catalyst-free carboxylation via the functionalization of benzylic C(sp3)–H bonds
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Scheme 9 UV-light-induced organic-photocatalyzed carboxylation via functionalization of C(sp3)–H bonds in benzyl amines
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Scheme 10 UV-light-induced dual-Ni/organocatalyzed carboxylation via functionalization of a benzylic C(sp3)–H bond
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Scheme 11 Visible-light-induced dual organo-photocatalyzed carboxylation via functionalization of benzylic C(sp3)–H bonds
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Scheme 12 Visible-light-induced dual-Ni/organocatalyzed carboxylation via the functionalization of C(sp3)–H bonds; HE = Hantzsch ester; l = linear; b = branched
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Scheme 13 Visible-light-induced Ir-photoredox-catalyzed carboxylation via the functionalization of C(sp3)–H bonds
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Scheme 14 Electrochemical carboxylation via functionalization of the α-C(sp3)–H bond in carbonyl compounds
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Scheme 15 Electrochemical carboxylation via functionalization of the benzylic C(sp3)–H bond in a benzyl alcohol