Decarboxylative Functionalization Research Articles

Visible-Light Photoredox-Catalyzed Direct Decarboxylative Functionalization of α-Keto Acids.

A novel and environmentally friendly photocatalytic strategy is presented for generating acyl radicals from benzoylformic acids, which are subsequently trapped by various sulfone-based SOMOphiles. This strategy provides a robust toolkit to access a variety of synthetically important functionalized aryl-ketone derivatives, which efficiently and directly construct acyl-S, acyl-Se, acyl-C, and acyl-N bonds. The broad substrate scope, excellent functional group compatibility, and mild reaction conditions make this protocol practical and attractive.

Electrooxidative Ni-catalyzed Decarboxylation of Arylacetic Acids towards the Synthesis of carbonyls under Air Conditions.

After systematic realization of decarboxylative functionalization of carboxylic acids under heating conditions in our group, we herein reported an electrochemical method for Ni-catalyzed decarboxylative oxygenation of arylacetic acids under open air conditions. The protocol provided corresponding carbonyls including aldehydes and ketones in moderate to satisfactory yields with good functional group tolerance, furthermore, the practicability and advantage of the method was highlighted through Ni-catalyzed oxidative decarboxylation of carboxylic acid-containing drugs and preformation of scalable transformation. Mechanistic studies demonstrated that the possible involvement of free radical intermediate in the conversion.

Light‐Induced Direct Decarboxylative Functionalization of Aromatic Carboxylic Acids

Aryl radicals are important intermediates in organic synthesis. The generation of these reactive species via direct decarboxylation of inexpensive and readily available aromatic carboxylic acids is an attractive goal. However, such a process intrinsically exhibits high energy barriers to overcome, which in consequence usually require precious metal catalysis, stoichiometric oxidants and harsh conditions, suffering from limitations such as poor functional group tolerance and low atom economy. In recent years, visible‐light‐induced photochemical reactions have provided new approaches to address this challenge. Three major strategies have been introduced in this emerging field: 1) one‐pot in‐situ activation of benzoic acids to generate intermediates such as benzoyl hypobromites or hypoiodites; 2) the use of specialized photocatalysts like biphenyl/1,4‐dicyanobenzene to promote decarboxylation through photo‐induced electron transfer or charge transfer processes; 3) photo‐induced LMCT (Ligand‐to‐Metal Charge Transfer) strategy where copper or iron salts coordinate to the carboxylate anion and generate aromatic radicals upon visible light excitation. On the basis of these three strategies, this review will systematically summarize the development of visible‐light‐induced direct decarboxylative functionalization of aromatic carboxylic acids, focusing on the reaction mechanism and substrate scope, and discuss their prospects in organic synthesis.

Photocatalytic Decarboxylative Functionalization of Cyclopropenes via Cyclopropenium Cation Intermediates

AbstractA photocatalytic decarboxylative functionalization of cyclopropenes is reported. Starting from a broad range of redox‐active ester‐substituted cyclopropenes, cyclopropenylphthalimides can be synthesized in the absence of a nucleophile. Alternatively, different carbon and heteroatom nucleophiles can be introduced. The transformation proceeds most probably through the formation of an aromatic cyclopropenium cation, followed by trapping with the nucleophiles.

Photocatalytic Decarboxylative Functionalization of Cyclopropenes via Cyclopropenium Cation Intermediates.

A photocatalytic decarboxylative functionalization of cyclopropenes is reported. Starting from a broad range of redox-active ester-substituted cyclopropenes, cyclopropenylphthalimides can be synthesized in the absence of a nucleophile. Alternatively, different carbon and heteroatom nucleophiles can be introduced. The transformation proceeds most probably through the formation of an aromatic cyclopropenium cation, followed by trapping with the nucleophiles.

Iron-Catalyzed, Light-Driven Decarboxylative Alkoxyamination.

An iron-catalyzed visible-light driven decarboxylative alkoxyamination is disclosed. In the presence of FeBr2 and TEMPO, a large array of carboxylic acids including marketed drugs and biobased molecules is turned into the corresponding alkoxyamine derivatives. The versatility of the latter offers an entry towards molecular diversity generation from abundant starting materials and catalyst. Overall, this method proposes a unified and general approach for LMCT-based iron-catalyzed decarboxylative functionalization.

Decarboxylative C-N Coupling of 2,2-Difluorobicyclo[1.1.1]pentane (BCP-F2) Building Blocks.

Described herein is our effort toward achieving the decarboxylative functionalization of 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. When compared with the nonfluorinated bicyclo[1.1.1]pentane (BCP) analogues, we discovered divergent reactivities. This is the first successful decarboxylative coupling of BCP-F2 building blocks reported via the photoredox mechanism.

An efficient platform for decarboxylative functionalization of carboxylic acids using sulfuryl fluoride: Pd-catalyzed decarboxylative dehydrogenation of alkanecarboxylic acids and decarboxylative cross-coupling of arenecarboxylic acids

An in situ SO2F2-mediated and palladium-catalyzed method is shown for the decarboxylative dehydrogenation of alkanecarboxylic acids and decarboxylative cross-coupling of arenecarboxylic acids, respectively.

Photocatalytic decarboxylation of free carboxylic acids and their functionalization.

Visible light mediated decarboxylative functionalization of carboxylic acids and their derivatives has recently emerged as a novel and powerful toolkit for small molecule activation in diverse carbon-carbon and carbon-hetero bond forming reactions. Naturally abundant highly functionalized bench-stable carboxylic acid analogs have been employed as promising alternatives to non-trivial organometallic reagents for mild and eco-benign synthetic transformation with traceless CO2 by-products. In this highlight article, we focus on the development of various photodecarboxylative functionalization strategies along with intra/inter-molecular cyclization via concerted single electron transfer (SET) or energy transfer (ET) pathways. Moreover, widely explored carboxylic acids are systematically classified here into four categories; i.e., α-keto, aliphatic, α,β-unsaturated, and aromatic analogs for a concise overview to the readership. The association of decarboxylative radical species with coupling partners to construct C-C and C-N/O/S/P/X bonds for each analogous acid has been presented in brief.

Enzymatic Resolution and Decarboxylative Functionalization of α-Sulfinyl Esters.

α-Sulfinyl esters can be readily prepared through thiol substitution of α-bromo esters followed by oxidation to the sulfoxide. Enzymatic resolution with lipoprotein lipase provides both the unreacted esters and corresponding α-sulfinyl carboxylic acids in high yields and enantiomeric ratios. Subsequent decarboxylative halogenation, dihalogenation, trihalogenation and cross-coupling gives rise to functionalized sulfoxides. The method has been applied to the asymmetric synthesis of a potent inhibitor of 15-prostaglandin dehydrogenase.

Photoredox‐Catalyzed Decarboxylative Bromination, Chlorination and Thiocyanation Using Inorganic Salts

AbstractDecarboxylative halogenation reactions of alkyl carboxylic acids are highly valuable reactions for the synthesis of structurally diverse alkyl halides. However, many reported protocols rely on stoichiometric strong oxidants or highly electrophilic halogenating agents. Herein, we describe visible‐light photoredox‐catalyzed decarboxylative halogenation reactions of N‐hydroxyphthalimide‐activated carboxylic acids that avoid stoichiometric oxidants and use inexpensive inorganic halide salts as the halogenating agents. Bromination with lithium bromide proceeds under simple, transition‐metal‐free conditions using an organic photoredox catalyst and no other additives, whereas dual photoredox‐copper catalysis is required for chlorination with lithium chloride. The mild conditions display excellent functional‐group tolerance, which is demonstrated through the transformation of a diverse range of structurally complex carboxylic acid containing natural products into the corresponding alkyl bromides and chlorides. In addition, we show the generality of the dual photoredox‐copper‐catalyzed decarboxylative functionalization with inorganic salts by extension to thiocyanation with potassium thiocyanide, which was applied to the synthesis of complex alkyl thiocyanates.

Decarboxylative Functionalization of β,γ‐Unsaturated Carboxylic Acids: New Perspective for the Synthesis of Functionalized Allylic Compounds

AbstractDue to the versatile reactivity of allyl moieties for further transformations and their omnipresence in biologically and pharmaceutically active molecules, significant efforts have been devoted to the efficient introduction of such groups into organic compounds. Although a large variety of allylating reagents have been successfully developed, development of new, efficient and environmentally benign allylating reagents remains in high demand. Recently, easily accessible β,γ‐unsaturated carboxylic acids have been explored as promising allylating agents in decarboxylative allylation reactions. This type of transformation provides facile access to various functionalized allyl compounds including those that are difficult to prepare using the classic allylating reagents with high efficiency and regiocontrol, and can be rendered enantioselective by choosing a suitable catalyst precursor and chiral ligand. Moreover, utilizing such allylating reagents allows for the discovery of novel transformations, especially under visible light photocatalysis.

Free Carboxylic Acids: The Trend of Radical Decarboxylative Functionalization

AbstractThe exceptional versatility of carboxylic acids has been extensively exploited in organic synthesis across several decades. There has been a recent upsurge of radical decarboxylative transformations. The process can be initiated under mild conditions, and the resultant radicals have orthogonal reactivities to closed‐shell species, thus providing immense opportunities for streamlining novel reactions. The use of free carboxylic acids is the most desirable owing to its high atom and step economy. Aiming to demonstrate the attractiveness of the strategy and to inspire chemists to tackle existing challenges, this review outlines the recent advances on radical decarboxylative functionalization of free carboxylic acids.

Carboxylic Acids as Adaptive Functional Groups in Metallaphotoredox Catalysis.

The development of palladium-catalyzed cross-coupling methods for the activation of C(sp2)-Br bonds facilitated access to arene-rich molecules, enabling a concomitant increase in the prevalence of this structural motif in drug molecules in recent decades. Today, there is a growing appreciation of the value of incorporating saturated C(sp3)-rich scaffolds into pharmaceutically active molecules as a means to achieve improved solubility and physiological stability, providing the impetus to develop new coupling strategies to access these challenging motifs in the most straightforward way possible. As an alternative to classical two-electron chemistry, redox chemistry can enable access to elusive transformations, most recently, by interfacing abundant first-row transition-metal catalysis with photoredox catalysis. As such, the functionalization of ubiquitous and versatile functional handles such as (aliphatic) carboxylic acids via metallaphotoredox catalysis has emerged as a valuable field of research over the past eight years.In this Account, we will outline recent progress in the development of methodologies that employ aliphatic and (hetero)aromatic carboxylic acids as adaptive functional groups. Whereas recent decarboxylative functionalization methodologies often necessitate preactivated aliphatic carboxylic acids in the form of redox-active esters or as ligands for hypervalent iodine reagents, methods that enable the direct use of the native carboxylic acid functionality are highly desired and have been accomplished through metallaphotoredox protocols. As such, we found that bench-stable aliphatic carboxylic acids can undergo diverse transformations, such as alkylation, arylation, amination, and trifluoromethylation, by leveraging metallaphotoredox catalysis with prevalent first-row transition metals such as nickel and copper. Likewise, abundant aryl carboxylic acids are now able to undergo halogenation and borylation, enabling new entry points for traditional, primarily palladium- or copper-catalyzed cross-coupling strategies. Given the breadth of the functional group tolerance of the employed reaction conditions, the late-stage functionalization of abundant carboxylic acids toward desired targets has become a standard tool in reaction design, enabling the synthesis of various diversified drug molecules. The rapid rise of this field has positively inspired pharmaceutical discovery and will be further accelerated by novel reaction development. The achievement of generality through reaction optimization campaigns allows for future breakthroughs that can render protocols more reliable and applicable for industry. This article is intended to highlight, in particular, (i) the employment of aliphatic and (hetero)aryl carboxylic acids as powerful late-stage adaptive functional handles in drug discovery and (ii) the need for the further development of still-elusive and selective transformations.We strongly believe that access to native functionalities such as carboxylic acids as adaptive handles will further inspire researchers across the world to investigate new methodologies for complex molecular targets.

A Unified Approach to Decarboxylative Halogenation of (Hetero)aryl Carboxylic Acids.

Aryl halides are a fundamental motif in synthetic chemistry, playing a critical role in metal-mediated cross-coupling reactions and serving as important scaffolds in drug discovery. Although thermal decarboxylative functionalization of aryl carboxylic acids has been extensively explored, the scope of existing halodecarboxylation methods remains limited, and there currently exists no unified strategy that provides access to any type of aryl halide from an aryl carboxylic acid precursor. Herein, we report a general catalytic method for direct decarboxylative halogenation of (hetero)aryl carboxylic acids via ligand-to-metal charge transfer. This strategy accommodates an exceptionally broad scope of substrates. We leverage an aryl radical intermediate toward divergent functionalization pathways: (1) atom transfer to access bromo- or iodo(hetero)arenes or (2) radical capture by copper and subsequent reductive elimination to generate chloro- or fluoro(hetero)arenes. The proposed ligand-to-metal charge transfer mechanism is supported through an array of spectroscopic studies.

Bio-carbon-layered CuO-catalyzed decarboxylative alkenylation of cyclic ethers

An efficient methodology for the direct decarboxylative functionalization of cinnamic acid derivatives with cyclic ethers has been developed by using biogenic CuO/C nanoparticles. This protocol is compatible with broad range of substrates.

Functionalization of C–H Bonds and Carboxylic Acids via Copper Catalysis

Key words copper catalysis - radical chemistry - hydrogen atom transfer - decarboxylative functionalization

Visible-light photoredox-catalyzed selective carboxylation of C(sp3)−F bonds with CO2

Visible-light photoredox-catalyzed selective carboxylation of C(sp3)−F bonds with CO2

Visible-Light-Induced Photocatalytic Oxidative Decarboxylation of Cinnamic Acids to 1,2-Diketones.

A concerted metallophotoredox catalysis has been realized for the efficient decarboxylative functionalization of α,β-unsaturated carboxylic acids with aryl iodides in the presence of perylene bisimide dye to afford 1,2-diketones.

Radical Decarboxylative Carbometalation of Benzoic Acids: A Solution to Aromatic Decarboxylative Fluorination.

Abundant aromatic carboxylic acids exist in great structural diversity from nature and synthesis. To date, the synthetically valuable decarboxylative functionalization of benzoic acids is realized mainly by transition-metal-catalyzed decarboxylative cross couplings. However, the high activation barrier for thermal decarboxylative carbometalation that often requires 140 °C reaction temperature limits both the substrate scope as well as the scope of suitable reactions that can sustain such conditions. Numerous reactions, for example, decarboxylative fluorination that is well developed for aliphatic carboxylic acids, are out of reach for the aromatic counterparts with current reaction chemistry. Here, we report a conceptually different approach through a low-barrier photoinduced ligand to metal charge transfer (LMCT)-enabled radical decarboxylative carbometalation strategy, which generates a putative high-valent arylcopper(III) complex, from which versatile facile reductive eliminations can occur. We demonstrate the suitability of our new approach to address previously unrealized general decarboxylative fluorination of benzoic acids.