Carboxylic Acids as Versatile Precursors: Advances in Decarboxylation Strategies for Modern Organic Synthesis

Manan S Patel

doi:10.1021/acsomega.5c09198

. 2026 Feb 12;11(7):11001–11048. doi: 10.1021/acsomega.5c09198

Carboxylic Acids as Versatile Precursors: Advances in Decarboxylation Strategies for Modern Organic Synthesis

Manan S Patel ^1,^*

PMCID: PMC12947015 PMID: 41768721

Abstract

Carboxylic acids serve as versatile precursors in modern synthesis, leveraging decarboxylative strategies to bypass traditional reactivity patterns and facilitate the generation of high-energy intermediates. This transformative approach enables streamlined molecular assembly and enhances structural diversification through the regioselective removal of CO₂. This review provides a high-level, comprehensive synthesis of recent breakthroughs in decarboxylation, transitioning from traditional thermal methods to cutting-edge reactivity paradigms. We critically evaluate diverse catalytic systems, including transition metal-catalyzed processes (Fe, Ni, Cu, Zn, Ag, Ti, Ce, Ru, and In), Pd-catalyzed cross-couplings, and the burgeoning fields of organocatalysis, photoredox catalysis, and electrosynthetic mediation. Beyond a mere survey of reaction conditions, this work dissects mechanistic intricacies and addresses the inherent challenges of regioselectivity and functional group tolerance. By highlighting the assembly of complex molecular architectures from these ubiquitous precursors, this review establishes a conceptual framework intended to catalyze the next generation of innovations in decarboxylative chemistry and to inspire the discovery of novel reactivity manifolds.

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1. Introduction

Carboxylic acids are abundant, stable, and often naturally occurring, making them ideal substrates for modern C–C and C-heteroatom bond-forming reactions expressly via decarboxylation. Decarboxylation, the process involving the removal of a carboxyl group (−COOH) customarily in a form of carbon dioxide (CO₂), plays a crucial role in organic synthesis and various molecular transformation. It serves as a powerful strategy to modify molecular frameworks by simplifying molecules, introducing structural diversity, and enabling the generation of reactive intermediates. In synthetic organic chemistry, decarboxylation is frequently employed in the preparation of alkanes, arenes, ketones, and olefins, often under mild and metal-catalyzed conditions. It allows for the conversion of readily available and stable carboxylic acids into valuable synthetic intermediates or final products. Importantly, decarboxylative cross-coupling reactions have emerged as a sustainable alternative to conventional organometallic approaches, reducing the need for prefunctionalized coupling partners.

In addition, decarboxylation is vivacious in medicinal chemistry and natural product synthesis, as it allows for fine-tuning of molecular lipophilicity and biological activity by removing polar functionalities. The decarboxylative strategies can also facilitate late-stage functionalization, which is particularly advantageous in drug development. Furthermore, recent advances in photoredox, electrochemical, and transition-metal-catalyzed decarboxylation have broadened its synthetic utility by enabling site-selective C–C and C-heteroatom bond formations. These methodologies have contributed significantly to the development of green and atom-economical processes, aligning well with modern sustainability goals in chemical manufacturing.

Moreover, decarboxylative coupling reactions have emerged as a powerful and sustainable alternative to traditional cross-coupling methodologies in organic synthesis. , These reactions utilize willingly available carboxylic acids or their valuable derivatives as coupling partners, eliminating the need for prefunctionalized organometallic reagents. This not only reduces cost and waste but also enhances atom economy and operational simplicity.

Decarboxylative strategies have expanded the toolbox of synthetic chemists, enabling transformations under mild conditions and showing broad functional group tolerance. They are particularly valuable in late-stage functionalization and in the development of pharmaceuticals, agrochemicals, and functional materials. Furthermore, decarboxylative couplings align with green chemistry principles by avoiding stoichiometric metal byproducts and toxic reagents. The development of catalytic systems involving palladium, copper, or nickel has further increased the efficiency and scope of these transformations.

2. Metal-Catalyzed Decarboxylation

2.1. Transition Metal-Catalyzed Decarboxylation

Metal-catalyzed decarboxylation has become a vital strategy in organic synthesis, enabling the direct conversion of carboxylic acids or their derivatives into value-added products by cleaving C–C bonds and releasing CO₂ as a benign byproduct. This approach is particularly attractive due to the abundance, low cost, and stability of carboxylic acids, making them excellent starting materials for constructing complex molecules. Transition metals such as palladium, copper, nickel, and silver play a crucial role in facilitating these transformations under relatively mild and sustainable conditions. Metal-catalyzed decarboxylation has found widespread application in the synthesis of pharmaceuticals, agrochemicals, natural products, and advanced materials. Additionally, it aligns with the principles of green chemistry by minimizing hazardous reagents and waste.

2.1.1. Fe-Catalyzed Decarboxylation

Akondi and coworkers reported a novel photoinduced Fe(OTf)₂/2,4,6-collidine-catalyzed alkylation of Morita-Baylis-Hillman (MBH) acetates 1 with carboxylic acids 2 in a regio- and stereoselective manner (Scheme and Figures and ). This method showcases a broad substrate scope, including diverse carboxylic acids and MBH acetates, as well as drugs and bioactive molecules, enabling the synthesis of densely functionalized cinnamates and acrylates 3. The reactions are conducted under oxidant-free conditions in the green solvent dimethyl carbonate, emphasizing sustainability. Control experiments suggest a plausible mechanism involving an Fe(II)–Fe(III)–Fe(II) catalytic cycle, providing insight into the reaction’s mechanistic pathway. A total of 44 compounds were reported, with yields up to 93%.

Mechanism of Fe(II)-catalyzed alkylation of Morita-Baylis-Hillman acetates.

Representative examples of olefin product (3).

2.1.2. Ni-Catalyzed Decarboxylation

Qian et al. have developed the first asymmetric Ni-catalyzed decarboxylative Mannich reaction of chiral imines, enabling the synthesis of β-trifluoromethyl-β-amino ketones 6 (Scheme and Figure ). This reaction exhibits a broad substrate scope of keto acids 4 and proceeds efficiently at room temperature, delivering excellent chemical yields and diastereoselectivities. Notably, this methodology offers a straightforward approach for the preparation of chiral trifluoromethylated β-amino ketones, including suitability for large-scale synthesis. In total, 25 compounds were obtained, showing yields between 70% and 99%.

Representative examples of β-trifluoromethyl-β-amino ketones (6).

2.1.3. Cu-Catalyzed Decarboxylation

Zou and coworkers developed a copper-catalyzed decarboxylative aminomethylation of indole-3-carboxylic acids 7 with 1,2-oxazetidines 8, enabling the efficient synthesis of structurally diverse 3-aminomethylindoles 9 or 10 in good to excellent yields (Scheme and Figure ). Furthermore, an innovative decarboxylative aminomethylation/cyclization cascade was achieved using a combination of copper and iron salts, facilitating the construction of complex γ-carbolines with high efficiency. Notably, one of the resulting products demonstrated dual-emissive properties, exhibiting both aggregation-caused quenching (ACQ) and aggregation-induced emission (AIE), highlighting its potential as a functional luminogen.

Representative examples of 3-aminomethylindoles (9 and 10).

Das et al. developed a one-pot, regioselective decarboxylative alkynylation of tetrahydro-β-carboline-1-carboxylic acid 11 under peroxide-free conditions (Scheme and Figures and ). This reaction exhibits high regioselectivity, favoring functionalization at the position-1 over the position-3 of tetrahydro-β-carboline. Notably, the reaction outcome can be tuned to afford either alkynylated 12 or enaminone products 13, depending on the choice of reagents. The transformation proceeds via a sequential mechanism involving decarboxylative iminium ion formation, followed by alkynylation and an oxidative rearrangement cascade, showcasing a versatile strategy for regioselective functionalization.

Possible pathway of Cu(I)-catalyzed decarboxylation of tetrahydro-β-carboline-1-carboxylic Acid.

Representative examples of alkynylated products (12) or enaminone products (13).

Gao et al. addressed the challenges of synthesizing α-acyloxy ketones 16, traditionally achieved via the O–H insertion of diazo compounds with carboxylic acids-a method limited by the preparation and storage issues of diazo compounds. They developed a Cu(OAc)₂-mediated decarboxylative coupling of 3-indoleacetic acids 14 with sulfoxonium ylides 15, offering a practical and efficient route to rapidly synthesize α-acetoxyl ketones (Scheme and Figures and ). In this reaction, Cu(OAc)₂ serves dual roles as an oxidant and as a source of acetate ions. Remarkably, products derived from the reaction of 5-methoxy-2-methyl-3-indoleacetic acid with various sulfoxonium ylides exhibited fluorescence properties, and several demonstrated antiproliferative activity against human cancer cell lines, highlighting the synthetic and biological significance of the method. 41 compounds were synthesized, and their yields observed up to 87%.

Mechanism of Cu(II)-mediated decarboxylative coupling of 3-indoleacetic acids with sulfoxonium ylides.

Representative examples of α-acetoxyl ketones (16).

Zhang et al. report the development of a highly atom-economical method for synthesizing chiral propargylic cyanides 18, which are key building blocks for introducing chiral centers into valuable products and complex molecules (Scheme and Figures and ). This approach employs a chiral copper complex catalyst and achieves the formation of propargylic radicals through the direct decarboxylation of propargylic carboxylic acids 17 without the need for preactivation. The method exhibits excellent selectivity, broad functional group compatibility, and scalability. The study reported 18 compounds, achieving yields in the range of 46–90% with an enantiomeric ratio up to 98:2. The catalytical cycle is initiated by the in situ generation of a hypervalent iodine(III) carboxylate species, derived from the propargylic acid substrate and PIDA, with the assistance of a base gives intermediate A. This activated substrate subsequently engages with the chiral copper(I) cyanide species through a Single-Electron Transfer (SET) process. This crucial step is postulated to generate the transient propargylic radical B alongside a copper(II) species. The copper(II) species is then hypothesized to react with TMSCN, yielding a more reactive copper(II) cyanide intermediate. This intermediate intercepts the propargylic radical B to form the copper(III) species C. Finally, the unsymmetrical propargylic cyanide product 18 is released via reductive elimination, simultaneously regenerating the active copper(I) catalyst, which is poised to enter the next catalytic cycle.

Possible pathway of Cu(II)-mediated asymmetric cyanation of propargylic radicals.

Representative examples of asymmetric cyanation product (18).

Jiang et al. developed a copper-catalyzed intermolecular cross-coupling cascade for synthesizing N-fused pyrrolo- or pyrido[1,2-a]imidazo[1,2-c]quinazoline scaffolds 21. This protocol utilizes 2-(2-bromoaryl)-1H-benzo[d]imidazole analogues 19 and proline or pipecolic acid 20 as substrates, achieving high efficiency and broad functional group compatibility (Scheme and Figure ). Notably, proline or pipecolic acid serves a dual role as both the ligand and reactant. The reaction proceeds through a consecutive mechanistic pathway involving Ullmann coupling, decarboxylation, oxidation, and dehydration, providing a streamlined and versatile approach to constructing these valuable frameworks.

Representative examples of pyrrolo or pyrido-imidazo-quinazolines (21).

Shankar et al. developed a Cu(II)-catalyzed decarboxylative oxidative [4 + 2] annulation of coumarin-3-carboxylic acids 22 with tert-propargylic alcohols 23. The reaction proceeds through the in situ formation of α,β-unsaturated carbonyl compounds via the Meyer-Schuster rearrangement (Scheme and Figure ). This indirect C–H functionalization strategy provides a versatile approach for synthesizing diverse naphthochromenone scaffolds 24 with good to excellent yields, showcasing its synthetic utility. Overall, 29 compounds were produced with yields spanning 56–89%.

Representative examples of naphthochromenones (24).

Li and colleagues developed a copper-catalyzed protocol for the direct and enantioselective decarboxylative cyanation of benzylic acids 27, addressing a significant challenge in asymmetric radical cyanation reactions. By employing a commercially available hypervalent iodine(III) reagent 26, the method achieves in situ activation of alkyl carboxylic acids 25, facilitating the formation of alkyl radicals under mild conditions without requiring prefunctionalization (Scheme and Figures and ). This approach enables the synthesis of structurally diverse chiral alkyl nitriles in good yields and with high enantioselectivities. Furthermore, the resulting chiral nitriles serve as versatile intermediates for subsequent transformations into valuable chiral compounds. A total of 44 compounds were reported, with yields ranging from 81% to 93%. The catalytic cycle is initiated by the in situ activation of the carboxylic acid 25 through ligand exchange with PhIO, forming the phenyliodine(III) dicarboxylate intermediate A with the assistance of an external base. Concurrently, the active copper(I) species is generated in situ via the reduction of the precatalyst Cu(acac)₂ by TMSCN in the presence of the chiral ligand L₁. The subsequent catalytic turnover begins with a Single-Electron Transfer (SET) process, wherein the Cu(I) species reduces intermediate A, leading to the release of CO₂ and PhI, and the formation of a benzylic radical. The copper(II) species is then postulated to react with TMSCN to form a more cyanide-rich copper(II) intermediate, which efficiently intercepts the benzylic radical to yield the transient copper(III) complex C. The desired chiral product is released via reductive elimination.

Plausible mechanism of hypervalent iodine(III) reagent promoted decarboxylative cyanation.

Representative examples of asymmetric cynation product (27).

Jiang and coworkers disclosed a tandem copper-catalyzed intermolecular decarboxylative cross-coupling cascade between o-bromobenzoic acids 28 and proline or pipecolic acid 29 (Scheme and Figure ). This protocol efficiently constructs a variety of synthetically valuable fused benzoxazinone scaffolds 30 with broad functional group compatibility. Additionally, mechanistic studies revealed a sequential pathway involving decarboxylation followed by a dehydration coupling process, highlighting the method’s efficiency and utility in complex scaffold synthesis. Notably, proline or pipecolic acid serves a dual role as both the ligand and reactant. The reaction proceeds through a consecutive mechanistic pathway involving Ullmann coupling, decarboxylation, oxidation, and dehydration, providing a streamlined and versatile approach to constructing these valuable frameworks.

Representative examples of fused dihydro-benzoxazinones (30).

Fu et al. developed a novel, waste-free protocol for the copper-catalyzed decarboxylative homocoupling of o-nitrobenzoic acids 31 under noble metal-free conditions. This method demonstrates broad functional group tolerance, accommodating both electron-donating and electron-withdrawing substituents, and delivers nitro-containing biaryl compounds 32 in moderate to satisfactory yields with high selectivity (Scheme and Figure ). Notably, this procedure serves as a complementary approach to previously established methods for synthesizing symmetrical 2,2′-dinitro-substituted biaryls. Eleven compounds were synthesized, and their yields varied from 34% to 72%.

Representative examples of 2,2’-dinitrosubstituted biaryls (32).

Gogoi et al. developed a Cu(I)-catalyzed method for synthesizing substituted 3-methyleneisoindolin-1-ones 35 via a decarboxylative cross-coupling of 2-halobenzamides 33 with aryl alkynyl acids 34, followed by a 5-exo-dig heteroannulation (Scheme and Figures and ). In this transformation, alkynyl acids serve as precursors to generate alkyne intermediates, facilitating the construction of this valuable heterocyclic scaffold. Notably, while 2-iodobenzamides react efficiently without a ligand, the use of a ligand is essential for 2-bromo substrates.

Possible pathway of synthesis of 3-methyleneisoindolinone.

Representative examples of substituted 3-methyleneisoindolinone (35).

Guo et al. reported a ligand-free, copper-catalyzed aerobic decarboxylative coupling of cyclic α-amino acids 36 with a variety of C–H nucleophiles 37, including indoles, naphthols, alkynes, ketones, and nitroalkanes, using an exceptionally low catalyst loading (1 mol %) (Scheme and Figure ). This straightforward catalytic system efficiently facilitated the formation of diverse C(sp³)-C(sp³), C(sp³)-C(sp²), and C(sp³)-C(sp) bonds, offering a direct approach to nitrogen-containing heterocycles 38. The practicality of the method was further validated by gram-scale synthesis and its application in a three-step synthesis of a Rad51 inhibitor, underscoring its synthetic utility and scalability.

Representative examples of pyrrolidines (38).

Kumar et al. developed a novel copper(I)-mediated intermolecular tandem decarboxylative C(sp³)-C(sp) bond formation via C–H activation, enabling the direct synthesis of α-substituted pyrrolidine-oxyindoles 42 under mild reaction conditions (Scheme and Figures and ). This environmentally friendly intermolecular direct alkynylation (IDA) provides a convenient and efficient synthetic pathway to pharmaceutically relevant pyrrolidine oxindoles, as well as polycyclic alkynylated di- and triketones. Moreover, the methodology is applicable to constructing the core structures of natural spiro-alkaloids, highlighting its versatility and synthetic utility. The study reported 14 compounds, achieving yields in the range of 66–82%.

Plausible mechanism of Cu(I)-catalyzed synthesis of alkynylated pyrrolidineoxyindoles.

Representative examples of alkynylated pyrrolidineoxyindoles (42).

Lin et al. have developed an innovative, practical, and environmentally friendly approach for synthesizing polyfluorobiaryls 45 via decarboxylative cross-coupling. This method utilizes readily available, nonvolatile potassium polyfluorobenzoates 43 and aryl iodides or bromides 44 in the presence of an MCM-41-immobilized 1,10-phenanthroline-copper (I) complex ([MCM-41-Phen-CuI]) as the catalyst (Scheme and Figure ). The heterogeneous copper catalyst, prepared through a simple and cost-effective procedure using commercially available reagents, exhibits comparable catalytic activity to the homogeneous CuI/Phen system. This protocol enables the efficient synthesis of various polyfluorobiaryls in good to excellent yields with a broad substrate scope, accommodating diverse polyfluorobenzoate salts and aryl halides. Furthermore, the catalyst can be easily recovered by filtration and reused for at least eight cycles without significant loss of activity, making the procedure both economically viable and environmentally sustainable. Overall, 70 compounds were produced with yields spanning up to 99%.

Representative examples of polyfluorobiaryls (45).

Pu et al. have developed a decarboxylative intramolecular C–O cross-coupling reaction for the synthesis of oxygen-containing heterocyclic compounds from lactones (Scheme and Figures and ). This methodology was effectively utilized to convert 3-arylcoumarins 46 into 2-arylbenzofurans 47, demonstrating its versatility and applicability in heterocyclic compound synthesis. A total of 24 compounds were reported, with yields ranging from 26% to 84%.

Possible pathway of Cu(I)-catalyzed synthesis of alkynylated pyrrolidineoxyindoles.

Representative examples of 2-arylbenzofuran (51).

Rong et al. developed an efficient approach for synthesizing thioesters via the decarboxylative coupling of α-oxocarboxylic acids 48 with disulfides or thiophenols 49, enabling the formation of C(sp²)-S bonds (Scheme and Figure ). The resulting thioesters 50 possess valuable properties as nucleophile acceptors, making them critical intermediates in organic synthesis.

Representative examples of thioesters (50).

Yan et al. reported a copper-catalyzed aerobic decarboxylative amination of arylacetic acids 52 with 2-aminobenzoketones 51 and ammonium acetate, enabling the synthesis of 2-arylquinazolines 53 in moderate to excellent yields (Scheme and Figures and ). This one-pot reaction achieves multiple C–N bond formations via C–H and C–C bond cleavage. Compared to earlier methods, this innovative approach offers several advantages: the use of cost-effective copper as the catalyst, operational simplicity, molecular oxygen serving as the sole oxidant, environmentally benign byproducts and a broad substrate scope. In total, 30 compounds were obtained, showing yields between 10% and 99%.

Plausible mechanism of Cu-promoted decarboxylative amination of arylacetic acids.

Representative examples of 2-arylquinazolines (53).

Yang et al. have developed a mild and efficient protocol for decarboxylative amidation, employing a combination of copper and AIBN. This method enables the convenient and selective synthesis of a series of (E)-amination products 56 in moderate to good yields (Scheme and Figure ). The strategy offers a valuable approach for constructing C–N bonds, and also advancing the understanding of decarboxylative cross-coupling reactions. Eleven compounds were synthesized, and their yields varied from 54% to 87%.

Representative examples of amidation Product (56).

The comparison table of copper-enable cascade reactions are represented in Table . It clearly shows the detail of coupling partner, the Cu-catalyst used, bases, solvents, reaction temperature and yield range of the particular reaction. A detailed mechanistic investigation in the research article revealed for Schemes , , and to clarify the nature of the active species and the pathway of bond formation, contradicting initial assumptions regarding radical involvement. Specifically, in the transformations described in Schemes and , the reaction mechanisms were definitively shown to proceed via nonradical pathways. Furthermore, the α-amino acid derivatives, l-proline and pipecolic acid, were identified as playing a sophisticated, 2-fold role in these systems, they function not only as the ligand to coordinate the metal center but also as a direct reactant that participates in the catalytic cycle. This dual functionality is critical for both the observed yield of the products. Similarly, the reaction delineated in Scheme was confirmed to proceed through a nonradical mechanism. Mechanistic probing established that the presence of a benzyl group on the N-atom of the cyclic amine is indispensable for initiating the transformation. This substitution is required to favor the formation of the crucial azomethine intermediate, which subsequently undergoes the key bond-forming step, thus overriding any potential radical initiation pathways and ensuring high functional group tolerance and chemo-selectivity in the reaction.

1. Juxtaposing of Copper-Catalyzed Reactions.

Coupling Partner	Catalyst	Base	Solvent	Temp. (°C)	Yield (%)
2-(2-Bromoaryl)-1H-benzo[d]imidazole + proline or pipecolic acid	CuI	Cs₂CO₃	DMF	110	49–92
o-Bromobenzoic acids + proline or pipecolic acid	CuI	K₃PO₄	DMF	120	62–81
Cyclic α-amino acids nucleophiles including indoles, naphthols, alkynes, ketones, and nitroalkanes	Cu₂(OH)₂CO₃	DBU	Toluene	110	50–92
Cyclic diketones + alkynes + proline	CuI	-	Water	100	65–82

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2.1.4. Zn-Mediated Decarboxylation

Le et al. reported a decarboxylative C(sp³)-Sb coupling of aliphatic carboxylic acid derivatives 57 with chlorostibines 58 to synthesize alkylstibines 59. This method operates without the need for catalysts, ligands, or bases, using zinc as a reductant (Scheme and Figure ). The reaction efficiently produces a range of benzyldiarylstibines and monoalkyldiarylstibines, demonstrating broad functional group tolerance, including chlorine, bromine, hydroxyl, amide, sulfone, and cyano groups. The feasibility of late-stage modifications and gram-scale synthesis highlights the practical applicability of this approach. The study reported 20 compounds, achieving yields in the range of 54–80%.

Representative examples of alkylstibines (59).

Tarui et al. have developed a mild and efficient decarboxylative aldol reaction involving potassium α,α-difluoro-β-keto carboxylates 60 and aldehydes 61. This method operates at a reaction temperature below 100 °C, enabling the synthesis of a wide range of biologically active α,α-difluoro-β-hydroxy ketones 62 in good to excellent yields (Scheme and Figure ). Notably, the reaction utilizes bench-stable salts, offering advantages over previous methodologies in terms of practicality and substrate scope. Overall, 19 compounds were produced with yields spanning 53–99%.

Representative examples of α,α-difluoro-β-hydroxy ketones (62).

2.2. Other Metal-Catalyzed Decarboxylation

2.2.1. Ag-Catalyzed Decarboxylation

Wang and colleagues introduced an innovative approach for free-radical coupling of carboxylic acids 64 with isocyanides 63, enabling the efficient synthesis of a diverse array of amides 65 via silver catalysis (Scheme and Figures and ). This protocol exhibits broad functional group tolerance, producing amide products in excellent yields across a wide range of substrates. Furthermore, this methodology significantly expands the scope of isocyanides in free-radical chemistry, paving the way for the development of new catalytic systems and synthetic applications. A total of 76 compounds were reported, with yields ranging from 38% to 94%.

Tentative pathway of decarboxylative preparation of amides.

Sridhar and colleagues reported a groundbreaking silver-catalyzed intramolecular annulation of N-acrolyl-2-(3-indolyl) benzimidazoles 66 with alkyl carboxylic acids 67 to construct complex fused-pentacyclic alkaloid scaffolds 68 or 69 (Scheme and Figure ). The reaction exhibits divergent reactivity depending on the substituents at the C₂ position of the indole moiety. This domino process involves decarboxylative alkylation followed by dearomative annulation, achieving excellent diastereoselectivity. Additionally, the reactivity of the tert-OH group in the resulting aza-enriched scaffolds enables further functionalization, enhancing their synthetic versatility.

Representative examples of fused pyrido-indolones (68 or 69).

Yu et al. developed a silver-catalyzed decarboxylative nitrooxylation via a radical-based mechanism. This reaction demonstrates broad substrate scope, accommodating nonactivated primary and secondary carboxylic acids 70, and provides a practical method for synthesizing a novel class of organic nitrates 71 with excellent functional group compatibility (Scheme and Figure ). Mechanistic investigations suggest that a high-valent silver(II) nitrate complex serves as a versatile NO₃ source, facilitating efficient C–O bond formation and enabling this innovative transformation. In total, 30 compounds were obtained, showing yields up to 80%.

Representative examples of organic nitrates (71).

Pei et al. reported a novel radical decarboxylation-initiated SH2′ reaction of β,β-difluoroenol sulfonates 73 (Scheme and Figure ). This transformation offers mild reaction conditions, a broad substrate scope, and the ability to perform late-stage modifications of drug molecules, enabling a versatile and mechanistically distinct synthesis of bioactive and synthetically valuable α,α-difluoroketones 74. Preliminary mechanistic studies reveal that the reaction involves a silver-mediated decarboxylative radical generation followed by radical-addition-induced β-elimination of the sulfonyl radical, highlighting its unique reaction pathway. 33 compounds were synthesized, and their yields varied from 31% to 80%.

Representative examples of α,α-difluoroketones (74).

Yu and coworkers developed a silver-catalyzed decarboxylative nucleophilic fluorination of carboxylic acids 75, offering an efficient route to a wide variety of valuable fluorinated motifs 76. This method operates under mild conditions, exhibits excellent functional group tolerance, and proves particularly useful for late-stage functionalization (Scheme and Figures and ). Unlike conventional electrophilic fluorination, this approach employs a readily available nucleophilic fluorinating reagent, delivering significant advantages in cost efficiency, substrate scope, and functional group compatibility, making it a valuable addition to fluorination methodologies. Overall, 35 compounds were produced with yields spanning 34–76%.

Possible mechanism of nucleophilic fluorination of aliphatic carboxylic acids.

Representative examples of fluorinated motifs (76).

Xie et al. have developed a silver-catalyzed decarboxylative remote fluorination enabled by a zwitterion-promoted 1,4-heteroaryl migration (Scheme and Figures and ). This method facilitates the efficient synthesis of a range of heteroaryl-tethered benzyl fluorides 78 with high regioselectivity under mild conditions. The zwitterionic nature of the substrate plays a crucial role in accelerating the 1,4-heteroaryl migration, which is key to determining the regioselectivity of this transformation. This strategy showcases an innovative approach to remote fluorination with broad synthetic utility. The study reported 23 compounds, achieving yields in the range of 30–74%.

Possible mechanism of silver-catalyzed fluorination.

Representative examples of heteroaryl-tethered benzyl fluorides (78).

Paul et al. present a substrate-controlled, silver-catalyzed strategy that interrupts traditional radical pathways of the iminyl radical, enabling diverse reaction outcomes (Scheme and Figure ). Benzylic groups in carboxylic acids 79 play a pivotal role in directing the reaction pathway, facilitating various transformations, including dimerization and hydrolysis, a 1,5-H shift followed by cascade radical cyclization, and direct N-(sp²) bond formation or aromatization. These pathways provide efficient access to a broad range of cyclic and acyclic ketones 81, quinolines 82, and phenanthridine derivatives 83. Notably, mechanistic studies supported by high-resolution mass spectrometry revealed the involvement of rare intermediates such as azines, oximes, and β-functionalized vinyl azides, distinguishing this approach from prior methodologies.

Representative examples of cyclic and acyclic ketones (81), quinolines (82), and phenanthridine derivatives (83).

Li et al. have introduced a C-centered radical-initiated bicyclization strategy for N-tethered 1,7-enynes 84, with cyclic carboxylic acid 85 enabling the efficient synthesis of polycyclic cyclopenta[c]quinolines 86 with two all-carbon quaternary stereocenters (Scheme and Figure ). This method employs a sequential silver-catalyzed decarboxylation, followed by a cascade of C-centered radical processes, including α,β-conjugate addition, 6-exo-dig cyclization, hydrogen abstraction, 5-endo-trig cyclization, and single-electron transfer (SET). The transformation demonstrates high diastereoselectivity and site-selective decarboxylative C(sp³)-H functionalization, providing access to structurally diverse spirocyclic cyclopenta[c]quinolones. The protocol’s broad substrate scope, functional group tolerance, and efficient bond-forming/annulation sequence establish it as a valuable tool for complex molecule construction. In total, 28 compounds were obtained, showing yields up to 75%.

Representative examples of polycyclic 3,4-dihydroquinolinones (86).

Chang et al. have established a versatile and highly selective method for the decarboxylative coupling of α-oxocarboxylates 87 with aryltrifluoroborates 88 using an Ag (I)/persulfate-catalyzed system (Scheme and Figure ). This approach highlights the utility of cost-effective Ag(I) catalysts in facilitating decarboxylation, with K₂S₂O₈ acting as an efficient promoter. The method represents a practical alternative to traditional ketone 89 synthesis in organic chemistry. Notably, this protocol enables the synthesis of chalcone and chromone derivatives, demonstrating broad applicability and potential for widespread use in synthetic applications. In total, 32 compounds were obtained, showing yields up to 94%.

Representative examples of ketones (89).

Cheng et al. demonstrated the utility of decarboxylative acylation in the functionalization and diversification of aryl ketone synthesis 92 (Scheme and Figures and ). Remarkably, their newly developed catalytic system proved effective without modifications to their previously reported decarboxylative method for aryl ketone synthesis. This transformation involves the direct coupling of α-oxocarboxylates 90 with arylboronic acids 91, facilitated by silver catalysis. The reaction exhibits good functional group compatibility and proceeds efficiently in aprotic polar solvents, highlighting its practicality and adaptability in synthetic applications. 32 compounds were synthesized, and their yields varied up to 95%.

Tentative pathway of silver-catalyzed decarboxylative acylation of arylglyoxylic acids.

Representative examples of aryl ketones (92).

Mai et al. have introduced a Cu/Ag bimetallic tandem catalytic system for the selective alkenylation or alkynylation of alkanes 95 via double decarboxylative cross-coupling reactions involving cinnamic acids or phenylpropiolic acid 93 and aliphatic acids 94 (Scheme and Figure ). This innovative approach, previously unreported, operates efficiently in aqueous solution using only catalytic amounts of metals. Notably, both substrates are inexpensive and readily accessible without requiring prefunctionalization.

Representative examples of olefins (95).

Suresh et al. reported a silver-catalyzed acylation of pyridine N-oxide 96 using α-oxocarboxylic acids 97 as acylating agents. This method enables the efficient synthesis of acylated heteroarene N-oxides 98, which are challenging to prepare via conventional approaches, achieving high yields (Scheme and Figures and ). The protocol demonstrates broad functional group tolerance and operates via a radical pathway, highlighting its synthetic utility and mechanistic significance.

Possible pathway of silver-catalyzed decarboxylative acylation of pyridine-N-oxides.

Representative examples of acylated heteroarene N-oxides (98).

Yang et al. have established a regioselective acylarylation method for cinnamamides 99, utilizing readily accessible α-oxocarboxylic acids 100 as acyl sources (Scheme and Figures and ). This decarboxylative coupling and cyclization reaction is characterized by low catalyst loading, mild reaction conditions, and excellent tolerance of diverse functional groups. The process enables the efficient synthesis of a range of valuable substituted dihydroquinolinones 101 in moderate to good yields with high stereoselectivity, all achieved in an aqueous solution. The study reported 25 compounds, achieving yields in the range of 41–95%.

Tentative mechanism of silver-catalyzed radical acylarylation of cinnamamides.

Representative examples of dihydroquinolinones (**101**).

2.2.2. Ti-Catalyzed Decarboxylation

Carboxylic acids are versatile synthetic building blocks, valued for their stability, structural diversity, and wide commercial availability. However, direct enantioselective deoxygenative functionalization of carboxylic acids remains relatively rare. Gutierrez and coworkers addressed this challenge by developing an enantioselective deoxygenative amino-cyanation of carboxylic acids 102 using an innovative Ti (IV)-based multicatalytic system (Scheme and Figures and ). This system enables the catalytic transformation of each C–O bond in carboxylic acids into C–C, C–N, and C–H bonds, yielding enantioenriched chiral α-amino nitriles 104 with high enantiomeric ratios (up to 98:2 er).

Plausible mechanism of enantioselective deoxygenative amino-cyanation of carboxylic acids.

Representative examples of enantioenriched chiral α-amino nitriles (**104**).

2.2.3. Ru-Catalyzed Decarboxylation

Propargyl cyclic carbonates 106 have gained recognition as versatile precursors in synthetic chemistry, though their application has traditionally been confined to transition metal-catalyzed substitution and cyclization reactions. Jana and coworkers expanded their utility by employing them as coupling partners in Ru(II)-catalyzed C–H annulation of benzoic acids 105 (Scheme and Figure ). This strategy enables the efficient synthesis of a wide range of biologically significant isocoumarin and isoquinolinone derivatives in good to excellent yields, using bench-stable and readily accessible precursors. Preliminary mechanistic studies revealed that the C–H metalation step is both reversible and rate-determining in the reaction pathway.

Representative examples of substituted-chroman-4-ones (**111**).

Bhattacharyya and coworkers expanded their utility by employing them as coupling partners in Ru(II)-catalyzed C–H annulation of benzoic acids 108 and benzamides (Scheme and Figure ). This strategy enables the efficient synthesis of a wide range of biologically significant isocoumarin and isoquinolinone derivatives 110 in good to excellent yields, using bench-stable and readily accessible precursors. Preliminary mechanistic studies revealed that the C–H metalation step is both reversible and rate-determining in the reaction pathway. The practical value of this methodology was further demonstrated through successful scale-up reactions and postfunctionalization experiments. The study reported 32 compounds, achieving yields up to 91%.

Representative examples of isocoumarins (**110**).

Zheng et al. have developed a ruthenium-catalyzed decarboxylative allylation of carbonothioates 111, achieving generally high yields. The Ru-catalyst offers chemo- and regioselectivities that often complement those of conventional palladium catalysts (Scheme and Figure ). This method is significant both for advancing the understanding of decarboxylative reactions and for providing a convenient synthetic route to biologically and pharmaceutically relevant compounds.

Representative examples of allyl(aryl)sulfane (**112**).

2.2.4. In-Catalyzed Decarboxylation

Sakai and coworkers developed an indium-catalyzed reductive bromination of carboxylic acids 113 using 1,1,3,3-tetramethyldisiloxane (TMDS) and trimethylbromosilane (Me₃SiBr) (Scheme and Figure ). This versatile reduction system demonstrated broad functional group tolerance, accommodating halogens, hydroxy groups, thioether moieties, and alkenes. Furthermore, the reaction pathway for the reductive bromination series 114 was elucidated through detailed time-course monitoring using ¹³C NMR spectroscopy, providing valuable mechanistic insights. The compounds were showing yields up to 97%.

Representative examples of bromoalkanes (**114**).

3. Decarboxylation via Coupling

Coupling reactions are fundamental in organic synthesis, enabling the formation of C–C and C-X bonds with high efficiency, selectivity, and functional group tolerance. These reactions, especially cross-coupling reactions such as Suzuki, Heck, and Sonogashira couplings, have revolutionized the synthesis of complex organic molecules, including pharmaceuticals, agrochemicals, and materials. Their ability to construct diverse molecular frameworks under relatively mild conditions makes them indispensable in both academic and industrial chemistry. For instance, the Suzuki–Miyaura reaction is widely used for biaryl synthesis, a key structural motif in many drugs and natural products (Miyaura and Suzuki, 1995). Additionally, the Nobel Prize in Chemistry 2010 awarded to Heck, Negishi, and Suzuki underscores the global recognition of their impact on modern chemistry (Nobel Prize, 2010). Overall, coupling reactions have accelerated drug discovery, facilitated late-stage functionalization, and contributed to green chemistry practices by minimizing byproducts and avoiding harsh conditions (Magano and Dunetz, 2011).

Azulene is an aromatic hydrocarbon and dark blue isomer of naphthalene which was discovered in 1863. It is known for its unique blue color and nonbenzenoid structure, consisting of fused five- and seven-membered rings. It exhibits unusual electronic properties, including a large dipole moment and visible light absorption, making it valuable in organic electronics, dyes, and photodynamic therapy. Its ability to stabilize charge and participate in π-conjugation also makes it a promising building block in materials science and medicinal chemistry.

Very few research articles available that worked with the functionalization of azulenes. Xu and coworkers established an efficient methodology for selective functionalization of azulene 115 at the second position via directed C–H activation. This approach utilizes readily available and scalable starting materials, enabling direct access to the second position 117 without generating regio-isomeric byproducts (Scheme and Figures and ). The reaction demonstrates broad functional group tolerance, including compatibility with various heteroarenes. The method showed good compatibility with a variety of diversified functional groups on both azulenes and aromatic iodides. Twenty-one compounds were synthesized, and their yields varied from 31% to 80%.

Plausible mechanism of Pd-catalyzed C–H arylation of azulene.

Representative examples of functionalized azulenes (**117**).

Acetylenes, or alkynes, are highly versatile compounds in organic synthesis due to their rich reactivity and ability to form multiple bonds. Their linear geometry and high electron density at the triple bond make them key intermediates in coupling reactions, cycloadditions, and functional group transformations. Acetylenes are essential in the synthesis of pharmaceuticals, agrochemicals, natural products, and advanced materials such as conductive polymers and nanostructures.

Liu and Szostak developed a palladium-catalyzed decarbonylative Sonogashira cross-coupling of carboxylic acids 118. In this approach, carboxylic acids are activated in situ by forming a mixed anhydride, which undergoes decarbonylation using a Pd(OAc)₂/Xantphos system to generate an aryl-Pd intermediate (Scheme and Figure ). This intermediate is subsequently intercepted by alkynes 119, enabling access to the conventional Pd(0)/(II) catalytic cycle with carboxylic acids serving as versatile and orthogonal electrophilic cross-coupling partners. The methodology provides an efficient route to construct C(sp²)-C(sp) bonds 120 and is applicable to the derivatization of pharmaceuticals. The study reported 21 compounds, achieving yields up to 98%.

Representative examples of internal alkynes (**120**).

Indoles are one of the most important heterocyclic structures in organic and medicinal chemistry due to their presence in a wide variety of natural products, pharmaceuticals, and bioactive compounds. Their unique aromatic structure allows for diverse functionalization, making them key scaffolds in drug design, including anticancer, anti-inflammatory, and antimicrobial agents. Indoles also play vital roles in biological systems, such as the neurotransmitter serotonin and the hormone melatonin.

Mohammadi et al. reported a unified strategy for the simultaneous construction of two C–C and two C–N bonds via a cascade process involving alkynoic acid 123 trifunctionalization, ortho C–H functionalization 121, and amination 122 (Scheme and Figure ). This sequential approach prioritizes regioselective alkyne insertion over decarboxylation, with the carboxyl group of alkynoic acid playing a key role in ensuring high regioselectivity during the carbopalladation step. The method provides a novel and efficient route to synthesize unsymmetrical 2,3-diaryl-substituted indole scaffolds 124 with excellent regioselectivity and has been demonstrated as suitable for gram-scale applications. Overall, 22 compounds were produced with yields spanning up to 80%.

Representative examples of unsymmetrical 2,3-diaryl-substituted indole scaffolds (**124**).

Fu et al. reported a ligand-free palladium-catalyzed, norbornadiene-mediated annulation reaction between iodoarenes 126 and methyl 2-haloarenecarboxylates 125. This sequential process involves intermolecular C–H arylation followed by intramolecular decarboxylative annulation, yielding a range of valuable phenanthrene derivatives (Schemes and and Figures and ). The protocol was further extended to the synthesis of triphenylenes using norbornene as a cocatalyst. In addition, the decarboxylation of methyl esters occurs through solvent-mediated cleavage of the C–Me–O bond, providing mechanistic insights and expanding the scope of this versatile methodology.

Representative examples of phenanthrenes (**127**).

Representative examples of triphenylene (**130**).

Cyclic compounds play a crucial role in the design and synthesis of drugs and materials, making their efficient construction a key focus in synthetic chemistry. Zhang and coworkers developed a highly efficient method for synthesizing cyclic compounds using readily available carboxylic acids as starting materials 131 (Scheme and Figure ). This approach involves intramolecular decarbonylative sp² C–H arylation, enabling the synthesis of a diverse array of five- and six-membered carbo- and heterocycles 132. The method exhibits a broad substrate scope with excellent functional group tolerance. Furthermore, scale-up experiments demonstrate its practicality and potential for application in organic synthesis. A total of 54 compounds were reported, with yields ranging up to 97%.

Representative examples of carbo- and heterocycles (**132**).

Zhou et al. have developed a palladium-catalyzed divergent cascade decarboxylative annulation of aryl iodides 133 and α-oxocarboxylic acids 134, using norbornene (NBE) derivatives as a controllable switch. When NBE serves as the mediator, the reaction proceeds through a Catellani pathway, enabling the synthesis of fluorenones 135 in moderate to excellent yields via sequential ortho–C-H arylation and ipso-decarboxylative acylation of aryl iodides (Scheme and Figure ). Substituting NBE with oxanorbornadiene (ONBD) facilitates the formation of dibenzo[a,c]cycloheptenones 136 through a retro-Diels–Alder reaction instead of ONBD release. The method’s synthetic utility is further illustrated through the diversification of the products, showcasing its broad applicability of the protocol.

Representative examples of fluorenones (**135**) and dibenzo[a,c]cycloheptenones (**136**).

Wang et al. developed a Pd-catalyzed decarboxylative cross-coupling method using zinc polyfluorobenzoates 137 as precursors for generating zinc reagents in situ. This approach enables the efficient synthesis of polyfluorinated biaryls 139 under mild conditions (Scheme and Figure ). The protocol features a broad substrate scope and excellent functional group tolerance. Its versatility was further demonstrated through the late-stage modification of drugs, biologically active molecules, and pesticides, highlighting its potential impact on drug discovery and development.

Representative examples of polyfluorinated biaryls (**139**).

Dehghan et al. have developed a base- and solvent-controlled divergent strategy for constructing polycyclic hydrocarbons. In this approach, norbornene acts as a reagent to enable the synthesis of norbornane-fused dihydrophenanthrenes 143, compounds notable for their biological activity. Remarkably, by altering the solvent and base, norbornene’s role shifts to that of a mediator or catalyst, allowing its exclusion from the final structure and facilitating the regioselective synthesis of triphenylenes 142 (Scheme and Figure ). Furthermore, in the absence of norbornene, an alternative pathway emerges, enabling the synthesis of unsymmetrically substituted triphenylenes 144 with exceptional regioselectivity. This reaction proceeds through a rare domino sequence involving decarboxylation, C–H activation, and annulation in a chemo- and regioselective manner.

Representative examples of triphenylenes (**150** and **152**) and norbornane-fused dihydrophenanthrenes (**151**).

Tripathi et al. developed a palladium(II)-catalyzed regio- and stereoselective three-component difunctionalization of alkynoic acids 145, enabling the synthesis of (E)-β-sulfonylacrylamides 148 using sodium sulfinates 146 and isocyanides 147 (Scheme and Figure ). The reaction proceeds via a decarboxylative isocyanide addition step, followed by sulfonylation, and demonstrates broad applicability to aromatic, heteroaromatic, and aliphatic alkynoic acids. This method showcases excellent functional group tolerance and high regio- and stereoselectivity. Density functional theory (DFT) calculations were conducted to elucidate the reaction mechanism and the selective formation of (E)-β-sulfonylacrylamides. The study reported 52 compounds, achieving yields in the range up to 82%.

Representative examples of (E)-sulfonylacrylamides (**148**).

Mondal et al. report a novel oxidative decarboxylative strategy for C–N cross-coupled α-ketoamidation 151 of α,β-unsaturated acids 149 and amines 150 (Scheme and Figure ). This method utilizes molecular oxygen as the oxygen source for the amide group and water as the oxygen source for the ketone, enabling a green and sustainable synthesis of α-ketoamides from readily available feedstock acids and amines. The process involves a photocatalyst operating via a reductive quenching cycle, while the palladium catalyst facilitates oxidative C–N bond formation. The methodology boasts a broad substrate scope, excellent functional group tolerance, and produces CO₂ and H₂O as the only byproducts, enhancing its efficiency and environmental appeal. The study reported 26 compounds, achieving yields up to 78%.

Representative examples of α-ketoamidation (**151**).

Li et al. developed a palladium-catalyzed annulation reaction between bay-diiodinated arenes 152 and o-chloroaromatic carboxylic acids 153, providing an efficient route to synthesize various polycyclic aromatic compounds 154 (Scheme and Figure ). This method is particularly effective for producing polyalkoxy-substituted polycyclic aromatic compounds, which are commonly used in discotic liquid-crystalline materials. Particularly, the synthesized compound 2,3,8,9,12,13-hexakis(hexyloxy)-5-azadibenzo[fg,op]tetracene exhibited favorable liquid-crystalline properties at room temperature, highlighting its potential for advanced material applications. The study reported 22 compounds, achieving yields up to 98%.

Representative examples of polycyclic aromatic compounds (**154**).

Ma et al. reported a synergistic dual-catalytic system comprising borinic acid and a palladium complex to mediate the allylation of 2-(2-azaaryl)acetic acids 155 with allylic electrophiles 156 under mild conditions. The decarboxylative allylation proceeds through the formation of a boron-bound enamine intermediate, which reacts with a π-allylpalladium species derived from the allylic electrophile (Scheme ). This methodology demonstrates high efficiency, delivering diallylation products 157 in excellent yields. Notably, when employing 2-(2-pyridyl)acetic acid with a C₃ substituent on the pyridyl ring, the reaction selectively affords monoallylation products 158, showcasing its unique selectivity.

Wang et al. demonstrated an electromagnetic mill (EMM)-promoted solid-state cascade Heck-type cyclization and decarboxylative coupling of propiolic acid 160 with (Z)-1-iodo-1,6-diene derivatives 159. This palladium-catalyzed reaction proceeds under solvent-free conditions without additional heating (Scheme and Figures and ). The collisions between ferromagnetic rods not only enhance mixing of the solid substrates with the catalyst system but also generate heat to accelerate the transformation. Conspicuously, this EMM-based strategy enables the construction of multiple bonds in the product form 161 in a single pot under mechanochemical conditions, showcasing its efficiency and sustainability. Overall, 24 compounds were produced with yields spanning up to 88%.

Possible pathway of Pd-catalyzed Heck-type cyclization.

Representative examples of 3-(3-arylprop-2-yn-1-yl)-1-tosyl-hydropyridines (**161**).

Saha et al. reported an efficient strategy for synthesizing a range of triarylmethanes via sp²–sp³ decarboxylative cross-coupling reactions of aryl carboxylic acids 162 with heteroaryl methyl iodides 163 (Scheme and Figure ). This methodology demonstrates notable functional group tolerance, yielding diverse triarylmethanes in moderate to good efficiencies through streamlined reaction steps. Additionally, the decarboxylative cross-coupling of heteroaryl methyl iodides offers a promising avenue for accessing biologically significant triarylmethane derivatives 164. Further exploration in this area is actively ongoing. Overall, 17 compounds were produced with yields spanning up to 80%.

Representative examples of triarylmethane (**164**).

Han et al. introduced an efficient palladium-catalyzed decarboxylative o-acylation of N-acetyl-1,2,3,4-tetrahydroquinolines 165 sing α-oxoarylacetic acids 166 as acyl sources (Scheme and Figures and ). The reaction demonstrates broad functional group compatibility and delivers aryl ketone derivatives 167 in good to excellent yields. This innovative approach offers a valuable method for synthesizing structurally significant aryl ketones with potential applications in organic synthesis and material science. Sixteen compounds were synthesized, and their yields up to 95%.

Plausible mechanism of Pd-catalyzed decarboxylative o-aroylation of N-acetyl-tetrahydroquinolines.

Representative examples of aryl ketones (**167**).

Karale et al. developed a straightforward, ligand-free palladium-catalyzed decarboxylative arylation of imidazo[1,2-a]pyridine-3-carboxylic acids 168 with a variety of aryl and heteroaryl bromides 169. This protocol offers a broad substrate scope and excellent functional group tolerance, enabling the synthesis of heteroaryl-hetero(aryl) motifs 170 (Scheme and Figure ). Notably, some of these motifs exhibited antibacterial activity against S. aureus. A total of 24 compounds were reported, with yields ranging from 20% to 92%.

Representative examples of 3-aryl-imidazo-pyridines (**170**).

Li et al. have introduced a pioneering palladium-catalyzed tandem Sonogashira/decarboxylative cross-coupling reaction using propiolic acid 171 and challenging aryl chlorides 172 and 173 as coupling partners. Remarkably, the reaction demonstrates good tolerance for ortho-sterically hindered aryl chlorides, yielding the desired products in moderate efficiencies (Scheme and Figure ). The substrate scope includes electron-rich, electron-neutral, and even electron-poor aryl chlorides. Additionally, the one-pot strategy for incorporatin unsymmetrical diarylalkynes 174, making this method a valuable tool in synthetic chemistry. In total, 24 compounds were obtained, showing yields up to 65%.

Representative examples of diarylalkynes (**174**).

Liu et al. have developed an efficient method for the palladium-catalyzed decarboxylative cross-coupling of electron-deficient arenes with mandelic acid 176, utilizing TBHP as an oxidant. This approach enables the direct acylation of sp² C–H bonds, offering a straightforward and effective strategy for constructing aryl ketones 177 (Scheme and Figure ). 25 compounds were synthesized, and their yields varied from 42% to 94%.

Representative examples of aryl ketones (**177**).

Yang et al. have showcased the use of PdCl₂.(CyPhine)₂ as an effective catalyst in the decarboxylative cross-coupling of alkynyl carboxylic acids 178 with a wide range of commercially available alkyl, aryl, and (hetero)aryl chlorides 179. This method demonstrates enhanced functional group tolerance and employs a straightforward protocol (Scheme and Figure ). As a complementary strategy to copper-free Sonogashira reactions, PdCl₂. (CyPhine)₂ was further utilized for the synthesis of symmetrical di(heteroaryl)alkynes 180 via a tandem Sonogashira/decarboxylative cross-coupling of propiolic acid with heteroaryl chlorides. The study reported 34 compounds, achieving yields up to 99%.

Representative examples of di(heteroaryl)alkynes (**180**).

4. Organo-Catalyzed Decarboxylation

Organocatalyzed decarboxylation has gained significant attention as a green and sustainable strategy in organic synthesis. Unlike metal-catalyzed processes, organo-catalysis avoids the use of toxic or expensive transition metals, making it more environmentally friendly and suitable for applications in pharmaceutical and fine chemical industries. This method enables the transformation of stable and readily available carboxylic acids into reactive intermediates, such as enolates or carbanions, which can undergo further bond-forming reactions.

These reactions are particularly valuable in the construction of complex molecular scaffolds under mild conditions. Organocatalyzed decarboxylation is often employed in enantioselective processes, expanding its utility in asymmetric synthesis and natural product derivatization. Moreover, it contributes to atom economy and functional group tolerance, aligning well with the principles of green chemistry.

Carboxylic acid functional groups are present in over 450 marketed drugs worldwide, underscoring their importance in pharmaceutical chemistry. Wu et al. reported a concise and environmentally friendly organic photoinduced method for the interconversion of carboxylic acids into their bioisosteres. This versatile strategy enables the efficient transformation of a wide range of substrates-including alkyl, (hetero)aryl, alkenyl acids 181, into primary sulfonamides 183, expanding the toolkit for drug development and modification (Scheme and Figures and ).

Tentative mechanism of conversion of carboxylic acids to sulfonamide bioisosteres.

Representative examples of sulfonamides (**183**).

Zhang and coworkers developed an organophotoredox catalytic system for the decarboxylative allylation of α-amino acids 184 and C-terminal carboxylate peptides, utilizing Morita-Baylis-Hillman adducts as allylic precursors 185 (Scheme and Figures and ). This metal-free approach operates under mild conditions and exhibits broad compatibility with diverse amino acids. The versatility of this method, particularly in chemical biology, has been demonstrated through its application in the ligation of bioactive peptide chains 186. Overall, 42 compounds were produced with yields spanning up to 93%.

Possible mechanism of conversion of carboxylic acids under metal-free condition.

Representative examples of products (**186**).

Xiao et al. developed a photocatalytic radical [4 + 2] cyclization method for the synthesis of structurally diverse polysubstituted tetrahydroquinolines 189 from N-aryl-α-amino acids 187 and various alkenes 188 (Scheme and Figure ). Utilizing a simple bipyridine as the catalyst, this strategy accommodates a wide range of N-aryl-α-amino acids as radical precursors and diverse electrophilic alkenes, including exocyclic terminal alkenes, acyclic terminal alkenes, and cycloalkenes. The method delivers 10 types of nitrogen-containing heterocyclic compounds across multiple frameworks with moderate yields and good diastereoselectivities. The scalability and postsynthesis transformations of the products demonstrate the practicality of this protocol. Mechanistic studies suggest a decarboxylative radical pathway involving a proton-coupled electron transfer (PCET) process. Key highlights of this approach include the use of a simple photocatalyst, mild reaction conditions, broad substrate scope, and its applicability for modifying natural products. A total of 48 compounds were reported, with yields ranging from 37% to 68%.

Representative examples of polysubstituted tetrahydroquinolines (**189**).

Davies et al. developed a photocatalytic approach for the one-step synthesis of γ-ketoacids 192 from α-ketoacids 190. The method utilizes maleic anhydrides 191 as traceless synthetic equivalents of acrylic acids, enabling selective cross-coupling through a dual decarboxylative mechanism, with molecular CO₂ as the sole byproduct (Scheme and Figures and ). This strategy was further extended to a highly regioselective three-component coupling with various alcohols, providing access to functionalized γ-ketoesters, showcasing its versatility and synthetic utility. In total, 23 compounds were obtained, showing yields between 37% and 99%.

Plausible mechanism of synthesis of γ-ketoacids.

Representative examples of γ-ketoacids (**192**).

Zhang et al. report a novel organophotoredox/DABCO catalytic system for the fluoroalkylation of activated allylic acetates 194 through a radical–radical coupling mechanism. This method operates under mild conditions, exhibits high selectivity, and demonstrates broad substrate compatibility (Scheme and Figures and ). Notably, it facilitates the incorporation of diverse bioactive molecules, FDA-approved drugs, and amino acid derivatives into the transformation. This approach significantly enhances the synthetic toolbox for constructing fluorine-containing molecules 195.

Possible mechanism of fluoroalkylation of activated allylic acetates.

Representative examples of fluorine-containing products (**195**).

Lin et al. developed a base-free, one-pot Curtius rearrangement facilitated by 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl azide (DMTN₃) and catalyzed by 4-(dimethylamino)pyridine (DMAP) (Scheme and Figures and ). This catalytic method efficiently converts a wide range of primary, secondary, and tertiary alkyl and aryl carboxylic acids 196 into alkyl or aryl isocyanates 197 with stereospecificity. The protocol is demonstrated for late-stage decarboxylative isocyanation of natural products and drug molecules, enabling rapid drug synthesis and the use of in situ generated DMTN₃. Mechanistic studies reveal that the reaction rate is influenced by the concentration of DMAP, ensuring mild, controllable reaction conditions suitable for diverse substrates.

Tentative pathway of DMAP-catalyzed one-pot curtius rearrangement.

Representative examples of isocyanates (**198**).

Mandler et al. reported a two-step methodology for synthesizing substituted bicyclo[1.1.0]butanes 202. The approach begins with a photo-Hunsdiecker reaction that produces iodo-bicyclo[1.1.1]pentanes 200 under mild, metal-free conditions at room temperature (Scheme and Figure ). These intermediates subsequently undergo nucleophilic substitution with nitrogen and sulfur nucleophiles, yielding a variety of substituted bicyclo[1.1.0]butane derivatives.

Representative examples of bicyclo[1.1.0]butanes (**202**).

Laha et al. report an unconventional approach to amide synthesis via decarboxylative amidation of aryl and heteroarylacetic acids 203 using N-hydroxysuccinimide (NHS) 204 and tert-butyl nitrite. This method efficiently produces both aliphatic and (hetero)aromatic amides 206 in satisfactory yields (Scheme and Figure ). Mechanistic investigations uncovered a novel pathway involving the formation of activated esters through traceless α-functionalized benzylic radicals, which subsequently react with amines in a one-pot process to yield the desired amides. The practical utility of this methodology is exemplified by a gram-scale synthesis of Moclobemide, demonstrating its scalability and applicability.

Representative examples of aromatic amides (**206**).

He et al. established a practical and efficient silver-mediated oxidative decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids 207, employing nucleophilic AgSCF₃ 208 as the CF₃S source and Selectfluor as the oxidant (Scheme and Figure ). This method is applicable to primary, secondary, and tertiary alkyl carboxylic acids under mild conditions, demonstrating broad functional group tolerance. The protocol provides an alternative and site-selective strategy for constructing C(sp³)-SCF₃ bonds in the final products 209, offering a valuable tool for synthetic applications.

Representative examples of (trifluoromethyl)sulfane scaffolds (**209**).

Kamal et al. developed a straightforward, mild, and efficient one-pot protocol for the decarboxylative aromatization of tetrahydro-β-carboline-3-carboxylic acids 210 to β-carbolines 211. This method utilizes the cost-effective oxidant N-chlorosuccinimide, achieving higher yields and serving as an alternative to traditional methods requiring harsh metal-based reagents or extensive heating (Scheme and Figure ). The protocol’s efficacy was demonstrated through the total synthesis of biologically active β-carbolines, including norharmane, harmane, and marine alkaloids such as eudistomin I, N, T, and U. Additionally, the method successfully aromatized tetrahydro-β-carboline esters to their corresponding β-carboline esters with excellent yields, highlighting its broad utility in synthesizing complex β-carboline derivatives. Twenty-one compounds were synthesized, and their yields varied from 78% to 95%.

Representative examples of 1-substituted-9H-pyrido-indoles (**211**).

5. Photoinduced Decarboxylation

Photoinduced decarboxylation has emerged as a powerful and sustainable strategy in modern organic synthesis. By harnessing visible light energy, this method enables the activation of carboxylic acids or their derivatives to generate reactive radical intermediates under mild, metal-free, or metal-assisted conditions. This approach is particularly attractive for its high functional group tolerance, minimal environmental impact, and compatibility with complex molecule synthesis. Photoinduced decarboxylation has found broad applications in pharmaceuticals, agrochemicals, and materials science, especially in radical cross-coupling, C–H functionalization, and heterocycle formation. Furthermore, it utilizing light as a traceless reagent and reducing the need for hazardous chemicals or high temperatures.

5.1. Transition Metal-Catalyzed Decarboxylation

5.1.1. Fe-Catalyzed Decarboxylation

Decarboxylative radical reactions have achieved significant success, but their catalytic systems often depend heavily on the specific radical acceptors, necessitating case-by-case reaction optimization. Hu et al. addressed this challenge by developing an iron-catalyzed protocol that facilitates the efficient decarboxylation of diverse carboxylic acids 212 for a broad spectrum of radical transformations (Scheme and Figure ). This operationally straightforward method proved compatible with a wide range of radical acceptors 213 (213a–213e), enabling the synthesis of structurally diverse products (214–218), including oxime ethers, alkenylation, alkynylation, thiolation, and amidation derivatives, with high efficiency.

Tentative pathway of radical-mediated decarboxylative C–C and C–S coupling.

Bis(trifluoromethyl)carbinols are highly valuable pharmacophores, but their synthesis remains challenging due to the limited availability of safe and efficient bis(trifluoromethyl)carbinolation reagents. Guo and coworkers addressed this issue by developing a method for hydrobis(trifluoromethyl)carbinolation 221 of alkenes 219, using stable and readily available 2,2-bis(trifluoromethyl)glycolic acid 220 as a dual source of the bis (trifluoromethyl)carbinol unit and a hydrogen atom (Scheme and Figures and ). This approach employs a photoinduced Fe-LMCT (ligand-to-metal charge transfer)-enabled radical decarboxylation mechanism, generating a key bis(trifluoromethyl)carbinol radical intermediate essential for the transformation. The study reported 39 compounds, achieving yields up to 79%.

Possible reaction pathway of synthesis of alkyl bis(trifluoromethyl)carbinols.

Representative examples of alkyl bis(trifluoromethyl)carbinols (**221**).

Dong et al. report a photoinduced iron-catalyzed method for the direct decarboxylative sulfonylation of carboxylic acids, offering an efficient approach to synthesize organic sulfones 225. Sulfones are a vital class of compounds with broad applications across various research fields, yet their direct synthesis via decarboxylation remains challenging, especially using iron as a catalyst (Scheme and Figures and ). This method utilizes a radical-based decarboxylation process, operating under mild, efficient, and user-friendly conditions. The protocol exhibits broad substrate compatibility, accommodating diverse carboxylic acids 222 and carbon electrophiles 224. A proposed mechanism involves iron-catalyzed decarboxylation, radical transfer, single-electron reduction, and subsequent nucleophilic attack, highlighting its synthetic utility and mechanistic innovation. Overall, 32 compounds were produced with yields spanning up to 88%.

Mechanism of iron-catalyzed sulfonylation.

Representative examples of organic sulfones (**225**).

Xiong et al. have reported an efficient photoinduced iron-catalyzed strategy for the cross-coupling of alkyl carboxylic acids 227 and acrylic acids 226, offering a versatile tool for synthesizing a wide range of alkenes with polar functional groups 228. This innovative methodology also extends to the preparation of ketones using α-keto acids (Scheme and Figures and ). Mechanistic studies have provided preliminary insights into the reaction pathway. The protocol demonstrates broad functionalization potential, presenting opportunities to streamline the synthesis of complex analogues relevant to drug discovery efforts. A total of 21 compounds were reported, with yields up to 92%.

Plausible mechanism of Fe(III)-promoted Csp2-Csp³ Ccross-coupling.

Representative examples of substituted alkenes (**228**).

Yang et al. developed an efficient visible-light-driven, iron-catalyzed decarboxylative C–N coupling product 231 between alkyl carboxylic acids 229 and NaNO₂ 230 under mild and photosensitizer-free conditions (Scheme and Figures and ). This methodology offers good to excellent yields, broad functional group tolerance, and straightforward operational simplicity. Preliminary mechanistic studies revealed that visible-light-activated iron catalysis facilitates the oxidative decarboxylation of alkyl carboxylic acids to generate alkyl radicals while simultaneously promoting the reduction of NO₂ ^– to NO, enabling the subsequent C–N radical coupling reaction. In total, 30 compounds were obtained, showing yields up to 99%.

100 — Tentative pathway of visible-light-driven iron-catalyzed decarboxylative C–N coupling reaction.

101 — Representative examples of oximes (**231**).

5.1.2. Ni-Catalyzed Decarboxylation

Sparr and coworkers developed a robust methodology for amide synthesis through photoredox- and nickel-catalyzed cross-coupling of readily accessible oxamic acids 233 with aryl bromides 232 (Scheme and Figures and ). This transformation, enabled by mild reaction conditions and the use of a widely applicable organic photocatalyst (4CzIPN), presents a practical alternative to precious metal-catalyzed aminocarbonylations 234. The method was successfully scaled to gram quantities, with mechanistic studies-such as carbamoyl radical trapping using a HAT catalyst in the presence of D₂O-confirming the involvement of carbamoyl radicals. Additionally, the methodology was extended to generate deuterated formamides, offering high deuterium incorporation across various oxamic acids. Nineteen compounds were synthesized, and their yields varied from 5% to 87%.

102 — Reaction pathway of nickel- and photoredox-catalyzed aminocarbonylation of aryl bromides.

103 — Representative examples of amides (**234**).

5.1.3. Cu-Catalyzed Decarboxylation

Chun et al. have developed a photoinduced copper-catalyzed enantioconvergent remote alkynylation of N-hydroxyphthalimide esters 235 with terminal alkynes 236, facilitated by a 1,4-heteroaryl migration (Scheme and Figures and ). This approach enables the synthesis of a wide range of heteroaryl-tethered chiral alkynes 237 with excellent regio- and enantioselectivities. A chiral-ligand-coordinated copper species serves a dual role as both the photoredox catalyst and the cross-coupling catalyst. The chiral ligand is useful for the generation of chirality into the final product. Notably, there was no desired product detected in the absence of chiral ligand. Additionally, the reaction was completely inhibited by the radical scavenger (2,2,6,6-tetramethylpiper idin-1-yl)oxyl (TEMPO), and corresponding trapping adduct was obtained in 53% yield, indicating that the radical decarboxylation process should be involved in this reaction. This innovative methodology establishes a new platform for enantioconvergent remote alkynylation reactions. The study reported 40 compounds, achieving yields up to 92% and ee up to 99%.

104 — Plausible mechanism of Cu(I)-promoted enantioconvergent remote alkynylation.

105 — Representative examples of heteroaryl-tethered chiral alkynes (**237**).

5.2. Other Metal-Catalyzed Decarboxylation

5.2.1. Ir-Catalyzed Decarboxylation

Zhuang et al. have developed a photoinduced method for the efficient synthesis of sulfonamides 239, which are key structures in pharmaceuticals, agrochemicals, and organocatalysts. This strategy utilizes (hetero)aryl carboxylic acid oxime esters 238 as substrates and proceeds through a one-pot cascade radical–radical cross-coupling facilitated by energy-transfer-mediated photocatalysis (Scheme and Figures and ). The method demonstrates broad substrate compatibility, including various (hetero)aryl substrates, and proves effective for the late-stage modification of pharmaceutical molecules, highlighting its versatility and synthetic utility. Overall, 31 compounds were produced with yields spanning up to 85%.

106 — Tentative reaction pathway of decarboxylative aminosulfonylation of aryl carboxylic oxime esters.

107 — Representative examples of sulfonamides (**239**).

Tan et al. developed a photoredox-catalyzed method for the difluoroalkylation of amino acids 242 via simultaneous decarboxylation and defluorination. This innovative approach utilizes readily available amino acids 241 and trifluoroacetophenones 240 as starting materials, avoiding the need for preactivation (Scheme and Figure ). The method enables the efficient synthesis of various difluoroketone-functionalized amines in moderate to high yields, providing versatile building blocks for further modification. The transformation proceeds through a single-electron transfer (SET) radical pathway, highlighting its mechanistic elegance and synthetic potential. Overall, 27 compounds were produced with yields spanning 28% to 91%.

108 — Representative examples of difluoro products (**242**).

Biswas et al. reported an efficient and versatile strategy for the hydroacylation of cyclopropenes, enabling the synthesis of diverse 2-acylcyclopropane 245 derivatives under mild conditions. This method exhibits high functional group tolerance and provides a novel, diastereoselective approach to the divergent synthesis of acylated cyclopropanes (Scheme and Figures and ). The protocol involves photoinduced decarboxylation of α-ketoacids 243 to generate acyl radicals, which subsequently add to cyclopropenes 244. The regioselective addition of acyl radicals to the least substituted olefinic carbon in a trans-selective manner further enhances its appeal, particularly for applications in natural product synthesis. A total of 39 compounds were reported, with yields ranging from 52% to 95%.

109 — Mechanism of photocatalyzed diastereoselective hydroacylation of cyclopropenes.

110 — Representative examples of cyclopropanes (**245**).

Venditto and Boerth highlight the utility of multicomponent radical-polar crossover (RPC) reactions, which integrate radical and polar bond-forming steps to achieve rapid molecular complexity in a single transformation (Scheme and Figures and ). Despite their potential, RPC reactions involving carbonyl π-bond electrophiles remain underexplored. In this study, the authors present a mild photoredox-catalyzed decarboxylative multicomponent RPC reaction that combines carboxylic acids 246, Michael acceptors 247, and carbonyl electrophiles 248. This approach enables the efficient synthesis of structurally diverse γ-amino butyric acid 249 derivatives and facilitates access to complex and biologically significant γ-lactam compounds. In total, 52 compounds were obtained, showing yields up to 87%.

111 — Reaction mechanism of synthesis of functionalized γ-amino butyric acids.

112 — Representative examples of functionalized γ-amino butyric acids (**249**).

Sun et al. introduced an environmentally friendly photocatalytic approach for generating acyl radicals from benzoylformic acids 250, which are subsequently intercepted by sulfone-based SOMOphiles (Scheme and Figures and ). This innovative strategy enables the efficient and direct construction of a variety of functionalized aryl-ketone 252 derivatives by forming acyl-S, acyl-Se, acyl-C, and acyl-N bonds. The method’s broad substrate scope, excellent functional group tolerance, and mild reaction conditions highlight its practicality and synthetic versatility, providing a valuable toolkit for advanced organic synthesis. The study reported 21 compounds, achieving yields in the range up to 92%.

113 — Photocatalyzed functionalization of α-keto acids.

114 — Representative examples of aryl ketones (**252**).

5.2.2. Ru-Catalyzed Decarboxylation

Lu et al. reported a practical and efficient method for synthesizing monofluoroalkenyl phosphine oxides 254 through a photoinduced decarboxylative and dehydrogenative coupling of α-fluoroacrylic acids 253 with phosphine oxides and phosphonates (Scheme and Figure ). This protocol demonstrated broad substrate compatibility, successfully converting various α-fluoroacrylic acids and P(O)H compounds, including those bearing functional groups such as tetrafluorobenzene and pentafluorobenzene, into the desired products with excellent E-stereoselectivity and satisfactory yields. Additionally, the method was extended to synthesize monofluoroalkenyl silanes 255 under analogous reaction conditions, showcasing its versatility.

115 — Representative examples of monofluoroalkenyl phosphine oxides (**254**) and monofluoroalkenyl silanes (**255**).

Lu et al. reported a novel and practical photoinduced methodology for the decarboxylative difluoroalkylation and perfluoroalkylation of α-fluoroacrylic acids 255. This approach utilizes a broad range of α-fluoroacrylic acids as versatile feedstocks, enabling the efficient synthesis of structurally significant difluoroalkylated 257, polyfluoroalkylated, and monofluoroalkenes with high Z-stereoselectivity under mild conditions (Scheme and Figure ). The protocol exhibits excellent functional group compatibility and offers a valuable platform for the late-stage modification of complex biologically active molecules. Overall, 38 compounds were produced with yields spanning up to 67%.

116 — Representative examples of difluoroalkylated Product (**257**).

Moczulski et al. have developed a doubly decarboxylative photocatalytic Giese reaction, showcasing a novel application of free carboxylic acid-activated olefins in radical transformations. The reaction efficiently utilizes various carboxylic acids, with chromone-3-carboxylic acids 259 serving as effective Giese acceptors (Scheme and Figure ). This process involves a dual decarboxylation mechanism, where the first decarboxylation initiates the radical cycle and the second completes it. The method provides access to biologically relevant 2-substituted-chroman-4-ones 260 in good to high yields under mild reaction conditions, highlighting its synthetic utility and efficiency. Twenty-five compounds were synthesized, and their yields varied from 18% to 82%.

117 — Representative examples of 2-substituted-chroman-4-ones (**260**).

5.2.3. Ce-Catalyzed Decarboxylation

Xiao and colleagues introduced a Ce(III)-catalyzed protocol for the selective decarboxylative oxygenation of carboxylic acids 261, enabling the synthesis of diverse products. This method allows a broad spectrum of carboxylic acids to be efficiently converted into aldehydes or ketones 262 and hydroperoxides 263 in good yields under mild conditions using molecular oxygen (Scheme and Figures and ). In addition, the selectivity of the reaction can be precisely controlled by altering the choice of base, offering a versatile approach to product tuning.

118 — Mechanism of Ce(III)-promoted synthesis of carbonyls and peroxides.

119 — Representative examples of carbonyls (**262**) and peroxides (**263**).

5.3. Dye-Mediated Decarboxylation

5.3.1. Eosin Y Decarboxylation

S-Alkyl dithiocarbamates, a vital class of sulfur-containing compounds, hold significant importance across various fields. However, synthetic methods starting from simple, readily available feedstocks under mild conditions to produce structurally diverse products remain limited. Dong and coworkers addressed this challenge by developing an efficient visible-light photocatalytic approach for synthesizing a wide range of S-alkyl dithiocarbamates 267 (Scheme and Figures and ). This method utilizes readily available alkyl carboxylic acids 264 (including primary, secondary, tertiary acids, and amino acids) and disulfide tetraalkylthiuram 266 as starting materials. The protocol is characterized by high efficiency, mild reaction conditions, broad substrate scope, and excellent functional group tolerance. Its potential utility is further demonstrated through sunlight-driven reactions, the use of water as a solvent, gram-scale synthesis, and the facile preparation of bioactive molecules.

120 — Tentative mechanism of conversion of acids to S-alkyl dithiocarbamates.

121 — Representative examples of S-alkyl dithiocarbamates (**267**).

Ishu et al. reported an efficient visible-light-induced method for synthesizing vinyl sulfones 272 through decarboxylative sulfonylation of cinnamic acids 268 or 270. This transformation utilizes sulfonylazides 269 or β-keto sulfones 271 as sulfonyl sources in the presence of cost-effective organic photocatalysts such as rhodamine B and eosin Y (Scheme and Figure ). The reaction is straightforward, operationally simple, and demonstrates broad substrate scope and excellent functional group compatibility.

122 — Representative examples of vinyl sulfones (**282)**.

5.3.2. Rose Bengal-Catalyzed Decarboxylation

Zhang et al. have developed a visible light-mediated decarboxylative amination method for N-protected indoline-2-carboxylic acids 273 and azodicarboxylate esters 274. The scope of this reaction extends to other cyclic systems containing α-oxy groups and N-Boc-tetrahydroisoquinoline carboxylic acids. A total of 13 novel amination products were synthesized with yields reaching up to 72%. The reaction is catalyzed by Rose Bengal, a metal-free photocatalyst, under mild conditions. This approach provides a versatile and general method for the selective amination of indolines at the C₂ position 275 (Scheme and Figure ). A total of 12 compounds were reported, with yields ranging from 22% to 72%.

123 — Representative examples of 2-amino indolines (**275**).

5.4. Organo-Catalyzed Decarboxylation

5.4.1. 4-CzIPN-Catalyzed Decarboxylation

The sustainable synthesis of spirocyclic compounds holds significant importance for the scientific community and the pharmaceutical industry. Yu and coworkers presented a carbamoyl radical-initiated intramolecular dearomative spirocyclization strategy to access spiro-cyclohexadiene oxindoles 277 under visible light irradiation (Scheme and Figures and ). This approach represents the first example of synthesizing I-substituted derivatives, enabling diverse downstream transformations. Furthermore, the method’s scalability, its application in late-stage drug modification, and the notable antitumor activity of the resulting products highlight its potential as a powerful platform for accelerating drug development. Twenty-seven compounds were synthesized, and their yields varied from 36% to 73%.

124 — Mechanism of photoredox-catalyzed synthesis of spiro-cyclohexadiene oxindoles.

125 — Representative examples of spiro-cyclohexadiene oxindoles (**277**).

Zuo et al. developed a visible-light-mediated decarboxylative coupling reaction of phenylacetic acid derivatives 278 using sulfur hexafluoride (SF₆) as an oxidant. This metal-free approach enables the synthesis of various bibenzyl derivatives 279 and complex all-carbon skeletons 280 (Scheme and Figure ). Moreover, the method not only provides an efficient synthetic route but also contributes to the utilization and degradation of SF₆, a potent greenhouse gas, highlighting its dual environmental and synthetic benefits.

126 — Representative examples of bibenzyl derivatives (**279**) and products (**280**).

Zhou et al. have developed a convenient method for synthesizing chromenopyrrolidines 283 under mild conditions through an organophotocatalyzed aerobic decarboxylative [2 + 2+1] annulation of chromones 281 with N-arylglycines 282 (Scheme and Figure ). Notably, N-arylglycines serve dual roles in this reaction as both radical precursors and methylene donors. Mechanistic investigations indicate that the annulation proceeds via a Giese-type radical addition followed by a Mannich-type pathway, providing insight into the reaction’s progression. The study reported 34 compounds, achieving yields in the range of 32% to 86%.

127 — Representative examples of chromenopyrrolidines (**283**).

Zhang et al. report a visible-light-driven, transition-metal-free allylic silylation reaction conducted under mild conditions. This approach utilizes an inexpensive organophotocatalyst, enabling an efficient and straightforward synthesis of substituted allylsilanes 286 (Scheme and Figures and ). Readily available allyl sulfones 284 and stable silanecarboxylic acids 285 serve as effective silyl radical precursors. Additionally, the method demonstrates broad applicability, including compatibility with vinyl sulfones for the synthesis of vinylsilanes. The strategy also highlights the potential of a silver catalytic system as an alternative pathway for the decarboxylative allylation of silanecarboxylic acids. Overall, 33 compounds were produced with yields spanning 34% to 88%.

128 — Plausible mechanism of organophoto-catalyzed synthesis of allylation of silanecarboxylic acids.

129 — Representative examples of allyl silanes (**286**).

Wei et al. reported a transition-metal-free, late-stage decarboxylative gem-difluoroallylation of carboxylic acids 287 with α-trifluoromethyl alkenes 288, enabled by organophotoredox catalysis. This strategy successfully incorporates both primary alkyl and heteroaryl acids under mild conditions, demonstrating broad functional group tolerance (Scheme and Figure ). The approach utilizes readily available feedstock materials and showcases its versatility through the late-stage functionalization of various acid-containing natural products and pharmaceutical compounds, highlighting its practical applicability in complex molecule synthesis.

130 — Plausible mechanism of synthesis of *gem*-difluoroallylation of primary alkyl acids.

Dong et al. present a photoredox-neutral radical–radical cross-coupling strategy for synthesizing 3-hydroxy-3-alkyloxindoles 292 from isatins 290 and benzyl carboxylic acids 291, employing 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as the photocatalyst (Scheme and Figures and ). This method offers a broad substrate scope and demonstrates excellent functional group compatibility, yielding 30 sterically hindered alcohols with moderate to excellent efficiency. The protocol relies on inexpensive, commercially available starting materials while avoiding the need for transition metals, additional oxidants/reductants, or harsh reaction conditions. This highlights its practicality, sustainability, and alignment with environmentally friendly synthetic practices. A total of 30 compounds were reported, with yields ranging up to 91%.

131 — Tentative mechanism of radical–radical cross-coupling of isatins and benzyl carboxylic acids.

132 — Representative examples of 3-hydroxy-3-alkyloxindoles (**292**).

Zhang et al. reported a catalytic cross-coupling method between carbon radicals and silicon radicals, providing an efficient, mild, and versatile route for synthesizing dibenzylic silanes 295. This transformation employs para-quinone methides 293 and silane-carboxylic acids 294 as stable silyl radical precursors, facilitated by an inexpensive organo-photocatalyst (Scheme and Figures and ). The reaction demonstrates broad functional group compatibility, accommodating both electron-donating and electron-withdrawing substituents. Mechanistic studies highlight the involvement of dibenzylic and silyl radicals, revealing a novel radical coupling pathway and offering fresh insights into C–Si bond formation strategies. In total, 26 compounds were obtained, showing yields between 25% and 96%.

133 — Plausible mechanism of organophotocatalyzed crosscoupling of C- and Si-radical.

134 — Representative examples of dibenzylic silanes (**295**).

Paixão and coworkers reported a mild and efficient method for synthesizing N-phenyl β-glycosyl β-lactams 299 incorporating drugs and natural products. The protocol employs metal- and photocatalyst-free diastereoselective functionalization of electrophilic 3-exomethylene β-lactams 297 with NHPI esters 296 via the formation of an electron donor–acceptor (EDA) complex (Scheme and Figures and ). This strategy showcases excellent functional group tolerance, scalability, and high diastereoselectivity, providing a versatile approach for functionalizing the C₃ position of the β-lactam core.

135 — Possible reaction pathway of photoinduced diastereoselective functionalization.

136 — Representative examples of N-phenyl β-glycosyl β-lactams (**299**).

5.5. X₂S₂O₈-Catalyzed Decarboxylation

Lee and colleagues reported the first direct decarboxylative of keto carboxylic acids 300 and activated alkenes 301 Giese aroylation utilizing a mechanistically distinct oxidative protocol. This innovative approach enables an efficient photocatalyst-free, light-mediated methodology (Scheme and Figures and ). The electron donor–acceptor (EDA) complex formed between the substrate and (NH₄)₂S₂O₈ is proposed as the key light-absorbing species. Twenty-three compounds were synthesized, and their yields varied up to 97%.

137 — Pathway of light-mediated direct decarboxylative giese aroylations.

138 — Representative examples of products (**302**).

Gao et al. developed an efficient and environmentally friendly method for synthesizing C₃-difluoroarylmethylated quinoxalin-2(1H)-ones 305 via a visible-light-induced decarboxylative difluoroarylmethylation. This protocol utilizes potassium 2,2-difluoro-2-arylacetate 304 as the difluoroarylmethyl source and operates in water under simple and mild reaction conditions (Scheme and Figure ). The reaction proceeds smoothly at room temperature, delivering the desired products in moderate to good yields while exhibiting broad tolerance for various substituent groups.

139 — Representative examples of difluoroarylmethylated quinoxalinones (**305**).

5.6. Catalyst-Free Decarboxylation

Shen and coworkers developed a novel and efficient visible-light-induced method for synthesizing functionalized 3-acyl-2H-indazoles 308. A key feature of this approach is the self-catalyzed energy transfer process between 2H-indazoles 306 and α-keto acids 307, eliminating the need for an external photocatalyst (Scheme and Figure ). This methodology offers several advantages, including a broad substrate scope, operational simplicity, and compatibility with mild reaction conditions, making it highly appealing for organic synthesis. 37 compounds were synthesized, and their yields varied up to 78%.

140 — Representative examples of 3-acyl-2H-indazoles (**308**).

Niu et al. highlighted the growing interest in efficient and sustainable methods for decarboxylative coupling reactions, given the structural diversity, low toxicity, and commercial availability of carboxylic acids 309. Despite this, challenges persist, particularly concerning the reliance on oxidants, catalysts, and prefunctionalization steps (Scheme and Figure ). In response, they developed a mild, catalyst- and additive-free method enabling direct electron transfer between alkyl carboxylic acids and excited-state substrates. This approach facilitates C–H alkylation of quinoxalin-2(1H)-ones 311 under simple and practical conditions, offering a streamlined and sustainable solution to these challenges. The study reported 36 compounds, achieving yields in the range of 31% to 96%.

141 — Representative examples of alkyl-quinoxalinones (**311**).

Rubanov et al. introduced a synergistic dual-photocatalytic platform integrating acridine and tetrabutylammonium decatungstate for carboxylic acid transformations. The method leverages in situ generated imines from aldehydes 314 and p-methoxyaniline 313, as well as other azomethines, as efficient radical acceptors (Scheme and Figure ). In this system, the decatungstate catalyst is proposed to enhance the turnover of the acridine photocatalyst through a hydrogen atom transfer (HAT) pathway, enabling streamlined radical generation and expanded reaction scope under mild conditions.

142 — Representative examples of substituted amines (**315**).

Serafino et al. developed an efficient and modular strategies for the synthesis of boron-containing compounds remains a central focus in modern organic synthesis due to their wide-ranging applications in medicinal chemistry, materials science, and catalysis. In this context, a two-step, one-pot protocol has been reported, integrating a visible-light-induced decarboxylative borylation of α- and β-amino redox-active esters 316 with bis(catecholato)diboron, followed by transamination with 1,8-diaminonaphthalene (DANH₂). This methodology affords a diverse library of boronamides 317 in moderate to excellent yields, highlighting its synthetic versatility (Scheme ). The photochemical decarboxylative borylation step demonstrates remarkable efficiency under both batch and continuous-flow conditions, enabling significantly reduced reaction times and the scalable preparation of DAN-boronates. Such an approach underscores the potential of visible-light photocatalysis to deliver atom-economical and operationally simple transformations in a sustainable manner.

6. Electrochemical Decarboxylation

A novel electrochemical strategy has been developed for the decarboxylative elimination of carboxylic acids 318 to alkenes 319 under mild, room-temperature conditions. This oxidant-free and environmentally friendly approach offers a sustainable alternative to conventional thermal decarboxylation methods (Scheme and Figure ). The protocol demonstrates broad substrate scope, enabling the efficient conversion of structurally diverse aliphatic carboxylic acids, including biologically active drugs, into their corresponding alkenes with good to excellent yields. Overall, 26 compounds were produced with yields spanning 47% to 76%.

143 — Representative examples of olefins (**319**).

Dash et al. developed an electrochemical method for the alkylation of azauracils 320 using N-(acyloxy)phthalimides (NHPI esters) 321 as accessible alkyl radical precursors, operating under metal- and additive-free conditions (Scheme and Figures and ). This approach demonstrates broad substrate compatibility, enabling the alkylation of various azauracils with a wide range of NHPI esters, including primary, secondary, tertiary, and sterically hindered derivatives, to afford the desired products 322 in good to excellent yields. The method is operationally simple, scalable, and versatile, making it suitable for both batch and flow setups, thus offering a practical and sustainable synthetic strategy. The study reported 47 compounds, achieving yields in the range of 53% to 92%.

144 — Tentative pathway of electrochemical C–H alkylation of azauracils.

145 — Representative examples of azauracils (**322**).

Lu et al. developed an electrochemical method for the decarboxylative alkoxy–alkoxycarbonylation of alkenes 323 using alcohols and monopotassium ethyloxalate 324 salts as substrates. This anodic oxidation process exhibits good functional group compatibility and proceeds via the formation of an acyl radical, which adds to an olefin to generate an alkyl radical (Scheme and Figures and ). The alkyl radical is further oxidized anodically to a carbocation, which is then trapped by alcohols, producing β-alkoxyalkanoates 325. The reaction efficiency was significantly enhanced by the addition of catalytic amounts of ammonium iodide, showcasing the practicality and versatility of the approach. Overall, 33 compounds were produced with yields spanning up to 88%.

146 — Reaction pathway of electrochemical decarboxylative alkoxy-alkoxycarbonylation of alkenes.

147 — Representative examples of β-alkoxyalkanoates (**325**).

Chen et al. developed an electrochemical method for the decarboxylative silylation of α,β-unsaturated carboxylic acids 326, enabling the synthesis of a range of alkenylsilanes 328 with excellent selectivity and satisfactory yields under metal- and external oxidant-free conditions (Scheme and Figures and ). Mechanistic investigations revealed that the silyl radical is generated through NHPI mediation, which produces the hydrogen atom transfer (HAT) reagent phthalimide N-oxyl (PINO) via a multiple-site concerted proton–electron transfer (MS-CPET) mechanism. This approach provides a sustainable and efficient strategy for alkenylsilane synthesis. A total of 26 compounds were reported, with yields ranging up to 86%.

148 — Possible mechanism of electrochemical decarboxylative silylation of α,β-unsaturated carboxylic acids.

149 — Representative examples of alkenylsilanes (**328**).

Xu et al. developed an electrochemical method for selective decarboxylation and dehydration of α-keto acids 330 with amines 329, providing straightforward access to amides 332 and α-ketoamides 331. These compounds are not only prevalent structural motifs in pharmaceuticals but also serve as versatile building blocks in synthetic chemistry (Scheme and Figure ). This efficient and environmentally friendly protocol operates without the need for metal catalysts or external oxidants. The method demonstrates a broad substrate scope and functional group tolerance, enabling the synthesis of various amides and α-ketoamides. Furthermore, it has been successfully applied to late-stage derivatization and can be safely scaled up for gram-scale production.

150 — Representative examples of ketoamides (**331**) and amides (**332**).

Walęcka-Kurczyk et al. have reported an optimized approach for the non-Kolbe electrolysis of N-protected α-amino acids using the ElectraSyn 2.0 system. This user-friendly and compact device enables efficient electrochemical decarboxylative methoxylation under mild conditions with excellent yields. By eliminating the need for custom-built electrochemical setups, this method overcomes a significant barrier to accessibility (Scheme and Figure ). Additionally, the standardized equipment ensures reproducibility across laboratories worldwide. The protocol aligns with sustainable and green chemistry principles, featuring a simple, low-waste workup process and the potential to utilize clean electricity, further enhancing its environmental appeal. In total, 20 compounds were obtained, showing yields between 92% and 99%.

151 — Representative examples of products (**334**).

7. Miscellaneous Decarboxylation

Shibata and colleagues developed an elemental sulfur-mediated approach for the synthesis of acyl fluorides 336 from carboxylic acids 335 using Selectfluor which turns into amide derivatives 337. This method enables the efficient preparation of a wide range of acyl fluorides while circumventing the formation of acid anhydrides. Investigations using ¹⁹F NMR spectroscopy suggest that the reactive species in this deoxyfluorination process are the in situ generated S₈-fluoro-sulfonium cation and neutral S₈ difluoride (Scheme and Figure ).

152 — Representative examples of amides (**337**).

Gu et al. reported a photoenzymatic approach for the decarboxylation of bulky secondary and tertiary carboxylic acids 338, catalyzed by engineered Chlorella variabilis fatty acid photodecarboxylase (CvFAP). Through rational design and directed evolution, the reactivity of wild-type CvFAP was enhanced, broadening its potential applications. Notably, the engineered CvFAP also facilitates light-driven kinetic resolution of α-substituted carboxylic acids. This work highlights the utility of photoenzymatic strategies for producing chiral building blocks and bioactive molecules from bulky carboxylic acids, opening new avenues for green and selective transformations (Scheme ).

Ye et al. developed a novel strategy for the incorporation of trifluoroacetyl functionality 342 into a diverse range of unsaturated bonds. The method utilizes PhI(OCOMe)₂ as an oxidant and a masked trifluoroacyl reagent 340 as the trifluoroacetyl radical precursor (Scheme and Figures and ). Through oxidative decarboxylation of the precursor, followed by a tandem radical process, this approach enables versatile transformations, including 5-exo-trig cyclization of N-arylacrylamides 341, direct C(sp²)-H trifluoroacetylation of quinolines, isoquinoline, 2H-indazole, and quinoxalin-2(1H)-ones, as well as C(sp)-H trifluoroacetylation of alkynes.

153 — Plausibel mechanism of iodine(III)-mediated trifluoroacetylation of a C(sp²)-H or C(sp)-H Bond.

154 — Representative examples of trifluoroacetyls (**342**).

Bloux et al. introduced a novel radioiodination method utilizing carboxylic acids 343 as radiolabeling precursors. The approach involves decarboxylation followed by the formation of organogold (I) intermediates, enabling efficient radioiodination of (hetero)arenes as well as cinnamic and phenylpropiolic acids (Scheme and Figure ). Furthermore, the study highlighted the extended stability of crude gold(I) organometallic compounds, underscoring their potential for prolonged and effective radiolabeling applications.

155 — Representative examples of iodoarenes (**344**).

Do et al. introduce a novel application of malonic acid and its derivatives 346, traditionally recognized as C₂ synthons, as C₁ synthons through a sulfur 347 and dimethyl sulfoxide-promoted double decarboxylation process (Scheme and Figure ). This strategy enables the synthesis of a broad array of thioureas, thioamides, and N-heterocycles 348 in good to excellent yields under mild heating conditions, with amines 345 serving as nucleophiles. This method expands the synthetic utility of malonic acid derivatives.

156 — Representative examples of substituted thioureas (**348**).

Zhang et al. developed a straightforward method for synthesizing diverse fluorinated indol-3-yl ketones 351 through direct decarboxylative fluoroacylation of indole carboxylic acids 349. This reaction operates under metal- and additive-free conditions and can be scaled up to the gram level. The methodology is characterized by its simplicity, high efficiency, exclusive selectivity, broad substrate compatibility, and ease of operation, aligning well with the principles of green chemistry and the demands of the modern pharmaceutical industry (Scheme and Figure ). Control experiments suggest the involvement of a radical mechanism in the tandem decarboxylative fluoroacylation sequence. Twenty-four compounds were synthesized, and their yields varied up to 97%.

157 — Representative examples of fluorinated indol-3-yl ketones (**351**).

Lee et al. reported a metal-free multicomponent strategy for synthesizing allyl amines 356 via a decarboxylative coupling combined with the Petasis reaction. This approach employs (E)-3-(2,4,6-trimethoxyphenyl)acrylic acid 353, various boronic acids 355, formaldehyde 353, and primary amines 354, operating efficiently without the need for metal catalysts (Scheme and Figure ). The study highlights the critical role of electron-donating substituents in cinnamic acid derivatives, which significantly enhance the reactivity and facilitate the transformations. The study reported 30 compounds, achieving yields up to 78%.

158 — Representative examples of allyl amines (**356**).

Rahman et al. developed an iodine-promoted method for C=C bond cleavage accompanied by decarboxylation and cross-coupling of cinnamic acids 357 with NH-sulfoximines 358. The reaction involves selective C=C bond cleavage followed by decarboxylation and oxidative sulfoximidation (Scheme and Figures and ). This metal- and base-free protocol utilizes dioxygen as the oxygen source, facilitated by tert-butyl hydroperoxide (TBHP) as the oxidant, yielding N-arylated sulfonimines 359 with good functional group tolerance and satisfactory yields. Overall, 35 compounds were produced with yields spanning up to 81%.

159 — Mechanism of iodine-promoted sulfoximidation of cinnamic acids.

160 — Representative examples of N-arylated sulfonimines (**359**).

Singh et al. introduced a novel strategy for amide 362 synthesis through sulfur-mediated decarboxylative coupling of cinnamic acids 360 with amines 361. This approach leverages the oxidative cleavage of the C=C bond, providing an efficient pathway to access amides (Scheme and Figure ).

161 — Representative examples of amides (**362**).

Sharma et al. presented a mechanochemical approach for initiating chemical reactions through mechanical forces such as milling, grinding, or shearing. Leveraging this concept, an oxidant-free and solvent-free method has been developed for synthesizing quinazolinones and benzothiazoles via stainless-steel-driven decarboxylative acyl radical generation from α-keto acids 363. This methodology enabled the preparation of a library of 2-arylquinazolinones 366 and 2-arylbenzothiazoles 367 in moderate to good yields under room-temperature conditions (Scheme and Figures and ). Mechanistic investigations, including control experiments and XPS studies, revealed that moderate abrasion of the steel balls facilitated the reduction of molecular oxygen by zerovalent iron, leading to the formation of a superoxide radical anion through a single electron transfer (SET) process.

162 — Pathway of synthesis of quinazolinones and benzothiazoles *via* decarboxylative method.

163 — Representative examples of quinazolinones (**366**) and benzothiazoles (**367**).

Yan et al. have developed a straightforward and efficient decarboxylative cyclization method for constructing imidazo[1,5-a]quinolines (370) using readily available starting materials under metal-free conditions (Scheme and Figure ). This approach significantly broadens the substrate scope of primary α-amino acids 369 compared to previous methods. Moreover, the absence of metal residues in the final products makes this method highly advantageous for pharmaceutical synthesis, ensuring cleaner and more practical applications. A total of 26 compounds were reported, with yields ranging from 33% to 90%.

164 — Representative examples of imidazo-quinolines (**370**).

Xing et al. have developed a mild and efficient method for C–S cross-coupling between aryl disulfides 372 and stable aliphatic carboxylates 371, achieved without the need for transition-metal catalysts. This versatile protocol enables the smooth decarboxylative thiolation of a broad range of primary, secondary, and tertiary (hetero)aryl acetates as well as α-cyano-substituted acetates, delivering products in moderate to excellent yields (Scheme and Figure ). Additionally, the methodology extends to the construction of C–Se bonds using aryl diselenides. DFT calculations suggest that the reaction pathway involves dienol formation, with proton transfer playing a key role. The mild reaction conditions and broad substrate compatibility make this approach highly practical for synthesizing biologically and pharmaceutically relevant molecules featuring aryl sulfur or selenium moieties. In total, 42 compounds were obtained, showing yields between 21% and 98%.

165 — Representative examples of products (**373**).

Guntreddi et al. reported a practical and efficient method for synthesizing 2-benzylbenzoxazoles, 2-benzylbenzothiazoles, and 2-arylquinoxalines 376 through the reaction of cinnamic acids 375 with 2-hydroxy-, mercapto-, or amino-anilines 374 via a decarboxylative C–N coupling followed by cyclization (Scheme and Figure ). This strategy notably employs aromatic amines in a Willgerodt-Kindler-type rearrangement. The methodology is operationally straightforward, utilizes readily accessible starting materials, and avoids the use of metals, solvents, and external oxidants, making it environmentally and economically appealing.

166 — Representative examples of 2-arylquinoxalines, 2-benzylbenzoxazoles, and 2-benzylbenzothiazoles (**376**).

Guo et al. developed a highly efficient one-pot method employing molecular sieves to mediate a sequential Knoevenagel condensation and decarboxylative Michael addition reaction. This approach involves the use of β-ketoacids 379 and MAHTs with isatylidene malononitriles, generated in situ from commercially available isatins 377 and malononitrile 378 (Scheme and Figure ). The protocol features a broad substrate scope and delivers 3,3-disubstituted oxindoles 380 with all-carbon quaternary centers in high yields. Remarkably, the reactions proceed under mild, base-free conditions with molecular sieves serving as the sole activator for both steps, highlighting its simplicity and practicality.

167 — Representative examples of 3,3-disubstituted oxindoles (**380**).

8. Conclusions

Carboxylic acids, owing to their versatile reactivity, have emerged as powerful and sustainable starting materials for a wide range of synthetic transformations. Decarboxylation serves as a key strategy to simplify molecular architectures, introduce structural diversity, and generate reactive intermediates for subsequent functionalization. Recent advances across metal-catalyzed, decarboxylative coupling, organocatalyzed, photoinduced, and electrochemical approaches highlight the expanding scope and applicability of this transformation. While notable progress has been achieved, further developments in catalyst design, reaction selectivity, and green methodologies are essential to fully harness the potential of decarboxylation in modern synthetic chemistry.

Supplementary Material

ao5c09198_si_001.pdf^{(596.5KB, pdf)}

Acknowledgments

The author gratefully acknowledges the Head, Department of Applied and Interdisciplinary Sciences, Sardar Patel University, Vallabh Vidyanagar, for providing the essential research facilities.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c09198.

Detailed nomenclature and structural representations for all abbreviated terms used in the manuscript are well detailed in the Supporting Information file (Tables S₁ and S₂) (PDF)

The author declares no competing financial interest.

Manan S. Patel dedicated this work to his beloved wife, Birva Patel.

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PERMALINK

Carboxylic Acids as Versatile Precursors: Advances in Decarboxylation Strategies for Modern Organic Synthesis

Manan S Patel

Abstract

1. Introduction

2. Metal-Catalyzed Decarboxylation

2.1. Transition Metal-Catalyzed Decarboxylation

2.1.1. Fe-Catalyzed Decarboxylation

1. Visible-Light-Promoted Iron­(II)/Lewis Base Catalyzed Alkylation of Morita-Baylis-Hillman Acetates.

1.

2.

2.1.2. Ni-Catalyzed Decarboxylation

2. Ni-catalyzed Asymmetric Decarboxylative Mannich Reaction for the Synthesis of β-Trifluoromethyl-β-Amino Ketones.

3.

2.1.3. Cu-Catalyzed Decarboxylation

3. Decarboxylative Aminomethylation of Indole-3-Carboxylic Acids via Strain Release-Driven Ring Opening of 1,2-Oxazetidines.

4.

4. Decarboxylative Transformations of Tetrahydro-β-Carboline-1-Carboxylic Acid.

5.

6.

5. Copper-Mediated Decarboxylative Coupling of 3-Indoleacetic Acids with Sulfoxonium Ylides for the Synthesis of α-Acetoxyl Ketones.

7.

8.

6. Copper-Catalyzed Asymmetric Cyanation of Propargylic Radicals via Decarboxylation of Propargylic Carboxylic Acids.

9.

10.

7. Copper-Catalyzed Consecutive Ullmann, Decarboxylation, Oxidation, and Dehydration Reaction for Synthesis of Pyrrolo or Pyrido-Imidazo-Quinazolines.

11.

8. Cu­(II)-Catalyzed Decarboxylative [4 + 2] Annulation of Coumarin-3-Carboxylic Acids.

12.

9. Copper-Catalyzed Enantioselective Decarboxylative Cyanation of Benzylic Acids Promoted by Hypervalent Iodine­(III) Reagents.

13.

14.

10. Copper-Catalyzed Decarboxylation Cross-Coupling Cascade Reaction for Synthesis of Fused Dihydro-benzoxazinones.

15.

11. Facile Synthesis of 2,2’-Dinitrosubstituted Biaryls through Cu-Catalyzed, Ligand-Free Decarboxylative Homocoupling of o-Nitrobenzonic Acids.

16.

12. Cu-Catalyzed Synthesis of Substituted 3-Methyleneisoindolinone.

17.

18.

13. Copper-Catalyzed Aerobic Decarboxylative Coupling between Cyclic Amino Acids and Diverse C–H Nucleophiles.

19.

14. Cu­(I)-Catalyzed Tandem Decarboxylative/C–H Activation Coupling of Cyclic Diketones, Proline And Alkynes: Synthesis of Alkynylated Pyrrolidineoxyindoles.

20.

21.

15. Highly Efficient Heterogeneous Copper-Catalyzed Decarboxylative Cross-Coupling of Potassium Polyfluorobenzoates with Aryl Halides.

22.

16. Copper-Catalyzed Decarboxylative Intramolecular C–O Coupling: Synthesis of 2-Arylbenzofuran from 3-Arylcoumarin.

23.

24.

17. Formation of C­(sp2)-S Bonds through Decarboxylation of Oxo-Carboxylic Acids.

25.

18. Copper-Catalyzed Aerobic Oxidative Decarboxylative Amination of Arylacetic Acids.

26.

27.

19. Copper-Catalyzed Decarboxylative Stereospecific Amidation of Cinnamic Acids with N-Fluorobenzenesulfonimide.

28.

1. Juxtaposing of Copper-Catalyzed Reactions.

2.1.4. Zn-Mediated Decarboxylation

20. Catalyst-Free, Zn-Mediated Decarboxylative Coupling of Chlorostibines to Access Alkylstibines with Stable C­(sp3)-Sb Bonds.

29.

21. Decarboxylative Aldol Reaction of Difluoro-Ketocarboxylate Salt for the Synthesis of Difluoroenolate.

30.

2.2. Other Metal-Catalyzed Decarboxylation

2.2.1. Ag-Catalyzed Decarboxylation

22. Approach for the Preparation of Amides through Decarboxylative Radical Cross-Coupling of Carboxylic Acids and Isocyanides.

31.

32.

23. Ag-Catalyzed Domino Decarboxylative Alkylation/Dearomative Annulation for the Preparation of Fused Pyrido-Indolones.

33.

24. Silver-Catalyzed Decarboxylative Nitrooxylation of Aliphatic Carboxylic Acids.

34.

25. Radical Decarboxylation of β,β-Difluoroenol Sulfonates to Access α,α-Difluoroketones.

35.

26. Decarboxylative Nucleophilic Fluorination of Aliphatic Carboxylic Acids.

36.

37.

27. Silver-Catalyzed Decarboxylative Remote Fluorination via a Zwitterion-Promoted 1,4-Heteroaryl Migration.

38.

39.

1. Visible-Light-Promoted Iron(II)/Lewis Base Catalyzed Alkylation of Morita-Baylis-Hillman Acetates.

8. Cu(II)-Catalyzed Decarboxylative [4 + 2] Annulation of Coumarin-3-Carboxylic Acids.

9. Copper-Catalyzed Enantioselective Decarboxylative Cyanation of Benzylic Acids Promoted by Hypervalent Iodine(III) Reagents.

14. Cu(I)-Catalyzed Tandem Decarboxylative/C–H Activation Coupling of Cyclic Diketones, Proline And Alkynes: Synthesis of Alkynylated Pyrrolidineoxyindoles.

17. Formation of C(sp²)-S Bonds through Decarboxylation of Oxo-Carboxylic Acids.

20. Catalyst-Free, Zn-Mediated Decarboxylative Coupling of Chlorostibines to Access Alkylstibines with Stable C(sp³)-Sb Bonds.

29. Synthesis of Polycyclic 3,4-Dihydroquinolinones via Site-selective Decarboxylative C(sp³)-H Functionalization.

30. Ag(I)/Persulfate-catalyzed Decarboxylative Coupling of Oxocarboxylates with Organo-trifluoroborates in Water under Room Temperature.

36. Ru(II)-Catalyzed Decarboxylative (4 + 2)-Annulation of Benzoic Acids and Benzamides with Propargyl Cyclic Carbonates.

45. Pd-Catalyzed Decarbonylative sp ² C–H Arylation for the Construction of Five- and Six-Membered Cyclic Compounds.

47. Pd-Catalyzed Decarboxylative Cross-Coupling of Zinc(II) Polyfluorobenzoates with Aryl Bromides to Access to Polyfluorinated Biaryls.

49. Palladium(II)-Catalyzed Decarboxylative Difunctionalization of Alkynoic Acids to Access (E)-Sulfonylacrylamides.

52. B/Pd Synergistic Catalysis for the Decarboxylative Allylation of 2-(2-Azaaryl)acetic Acids.