Carbonylation refers to the reaction of introducing a carbonyl functional group into a molecule to construct carbonyl-containing compounds (such as aldehydes, ketones, esters, etc.)^[1⇓-3]. Since its first report in 1938^[4], carbonylation has been widely concerned by researchers, with new types of reactions emerging continuously, and oxidative carbonylation is one of them. Oxidative carbonylation is a type of carbonylation reaction that requires the addition of an equivalent amount of oxidant^[5]. Its characteristic lies in the fact that traditional carbonylation uses halohydrocarbons^{[6⇓⇓⇓⇓-11]}, epoxides^{[12⇓⇓-15]}, olefins^{[16⇓⇓⇓-20]}, and other highly reactive compounds as substrates for carbonylation reactions, while oxidative carbonylation can achieve the carbonylation of carbon-hydrogen bonds^{[21⇓⇓⇓-25]}. Compared to structures such as epoxides and olefins, carbon-hydrogen bonds, as a basic component of organic substances, have a wide range of sources. It can be seen that oxidative carbonylation has a broader application scope and more diversified product structures.

The oxidation process is a key factor in ensuring the efficient progress of the oxidative carbonylation reaction. For this, scientists have developed various oxidation systems, including organic oxidants^{[26⇓⇓⇓-30]}, inorganic oxidants^{[31⇓⇓⇓⇓-36]}, and electrochemical oxidation^{[37⇓⇓-40]}. In recent years, with the destruction of our ecological environment and the worsening of environmental pollution, the treatment of pollution and environmental protection have become urgent, and green chemistry has become the main means to solve environmental problems^[41-42]. Oxygen, as a minor component of the atmosphere, is a natural and environmentally friendly oxidant, and its participation in oxidative carbonylation meets the development requirements of green chemistry. In addition, the carbonyl source in carbonylation reactions should also meet the requirements of green chemistry. Carbon monoxide, a common C1 substance, has the highest atomic utilization rate as a carbonyl source in carbonylation reactions.

Alkynes, as a class of widely occurring unsaturated compounds in nature, have significant application value in the field of organic synthesis. The carbon-carbon triple bond in their structure can be used to prepare multifunctional alkenes and alkane compounds through reactions such as addition. Terminal alkynes are a type of alkyne with the carbon-carbon triple bond located at the end of the chain. Their sp-hybridized triple bond has strong electron-withdrawing ability, making the terminal alkyne hydrogen prone to react with metal catalysts to form the corresponding alkyne-metal compounds, which then undergo coupling reactions^[43⇓-45]. Due to the excellent reactivity of the sp carbon-hydrogen bond under transition metal catalysis, terminal alkynes have also attracted attention in the field of oxidative carbonylation, with relevant achievements being reported. This paper introduces the oxidative carbonylation of terminal alkynes according to the types of nucleophiles and raw materials, focusing on explaining the mechanisms of metal-catalyzed carbonylation and metal oxidation, and elaborating on the application of these reactions in the synthesis of natural molecules. Finally, it provides an outlook on the future development of this field.

Oxidative carbonylation of terminal alkynes refers to the reaction where terminal alkynes react with carbon monoxide and nucleophilic reagents under metal catalysis to produce unsaturated carbonyl compounds. This type of reaction typically uses palladium catalysts. On one hand, palladium catalysts exhibit excellent reactivity in coupling reactions involving alkynes^[46⇓-48]; on the other hand, compared to other metals, palladium is more easily oxidized into divalent palladium in oxidative coupling reactions, which can continue to catalyze, making it widely used in oxidative carbonylation reactions^{[49⇓⇓-52]}. The process of such reactions, as shown in Figure 1, involves terminal alkynes first reacting with carbon monoxide and nucleophilic reagents under palladium catalysis to form carbonyl products and zero-valent palladium, after which the zero-valent palladium is oxidized by oxygen or other oxidants into divalent palladium to continue catalyzing the carbonylation reaction (Figure 1). Alcohols or amines are commonly used as nucleophilic reagents, thereby subdividing oxidative carbonylation into oxidative alkoxy-carbonylation and oxidative amine-carbonylation reactions.

2-alkynes are commonly used in the synthesis of functional organic molecules and bioactive molecules. The main preparation method involves the dehydrogenation of terminal alkynes under basic conditions to generate acetylide anions, which then react with haloformates. However, due to the weak acidity of the acetylenic hydrogen in terminal alkynes (pKa ~24), strong bases such as butyllithium are typically required for the dehydrogenation process, making the reaction conditions harsh, limiting the substrate scope, and posing significant safety risks. In contrast, the oxidative carbonylation method takes advantage of the ease with which metal catalysts can form acetylides from terminal alkynes, avoiding the use of highly hazardous strongly basic organometallic reagents, offering milder reaction conditions, and exhibiting high functional group tolerance.

The oxidative carbonylation of terminal alkynes was first reported in 1980^[44,53]. They used palladium chloride as a catalyst and copper chloride as an oxidant to achieve the carbonylation reaction of terminal alkynes, carbon monoxide, and alcohols (Figure2). In this process, copper chloride plays a crucial role. On one hand, it acts as an oxidant, oxidizing the zero-valent palladium produced during the reaction back to divalent palladium, which continues to catalyze the carbonylation reaction; on the other hand, after being reduced, copper chloride forms cuprous chloride, which can react with terminal alkynes under basic conditions to form acetylide, thus accelerating the reaction rate.

The above reaction requires the use of more than equivalent amounts of copper chloride as an oxidant to complete the carbonylation, which is costly and results in a large amount of copper salts that make post-treatment difficult. For the development of cheaper oxidants, it was reported in 1994 that an oxidative alkoxycarbonylation reaction of terminal alkynes with oxygen participation^[45,54]. This reaction proceeds using palladium chloride and copper chloride as catalysts, and lithium chloride as an additive. The reaction mechanism, as shown in Figure 3, involves the initial reaction between the terminal alkyne and copper chloride to form an acetylide copper and hydrogen chloride, followed by a transmetalation process between the acetylide copper and palladium chloride, yielding an acetylide palladium(II) chloride and copper(I) chloride. The acetylide palladium(II) chloride then undergoes carbonylation with carbon monoxide to produce an acetyl palladium(II) chloride species, which reacts with methanol to form an acetyl alkoxy palladium(II) intermediate. This intermediate undergoes reductive elimination to yield the product, a 2-alkynoate, and zero-valent palladium. The oxidation process of zero-valent palladium is similar to that in the Wacker reaction, where copper(I) chloride is first oxidized by oxygen to copper(II) chloride, which then oxidizes zero-valent palladium to palladium(II) chloride, while being reduced back to copper(I) chloride, completing the cycle. The cycling of the copper catalyst is achieved through oxygen, so only catalytic amounts of copper(I) chloride are needed in the reaction, making the oxidative alkoxycarbonylation reaction greener and more environmentally friendly, laying the foundation for subsequent research.

In 1999, the Ishii group^[55] developed a novel oxidative alkoxycarbonylation catalytic system. Using palladium acetate, chloranilic acid, and ammonium poly(molybdovanadophosphate) (NPMoV) as catalysts, and methanol as solvent, 2-alkynoates were prepared under acidic conditions (Figure 4). During the solvent screening process, it was found that using 1,4-dioxane instead of methanol selectively produced maleic anhydride-like compounds. Prior to this, the Alper group^[56] had reported a method for preparing maleic anhydride under similar reaction conditions, suggesting that water was a key factor in the formation of maleic anhydride. Based on this, Ishii et al. proposed a reaction mechanism where palladium acetate reacts with carbon monoxide and methanol or water to form acylpalladium(II), which then adds to the terminal alkyne triple bond to yield an alkenylpalladium(II) intermediate. When methanol is used as the solvent, this palladium(II) intermediate undergoes β-hydrogen elimination to produce 2-alkynoates and palladium(0); if the reaction is carried out in 1,4-dioxane, the alkenylpalladium(II) intermediate continues to react with carbon monoxide through carbonylation, followed by reductive elimination to generate anhydrides and palladium(0). For the oxidation process of palladium(0), both chloranilic acid and NPMoV act as co-oxidants. First, oxygen oxidizes NPMoV into its oxidized state, which then oxidizes chloranilic acid into chloranil, while itself being reduced back to NPMoV. Next, chloranil oxidizes palladium(0) into palladium(II), and is itself reduced back to chloranilic acid, participating in the continuous oxidation reaction cycle. This reaction features mild conditions, high functional group tolerance, and a broad substrate scope.

Heterogeneous catalysts, characterized by their ease of separation from the product and recyclability, hold significant value in industrial applications. Developing heterogeneous catalysts for oxidative carbonylation reactions is a crucial direction for achieving industrialization. In 2000, Giannoccaro et al.^[57] reported on the heterogeneously catalyzed terminal alkyne oxidative alkoxycarbonylation reaction (Figure 5). They prepared a heterogeneous catalyst ZrP-Pd by embedding palladium into zirconium phosphate, which was then applied to the oxidative alkoxycarbonylation of phenylacetylene. During the optimization of reaction conditions, it was found that using different solvents and bases could selectively produce various carbonylation products. When methanol was used as the solvent with the addition of triethylamine as a base, methyl phenylacetylate was obtained; without triethylamine, dimethyl maleate was produced; if acetonitrile was used as the solvent, the product was maleic anhydride. Regarding the mechanism, they proposed that the dicarbonylation mechanism was consistent with that reported by Ishii et al., where the palladium catalyst first reacts with carbon monoxide and water or alcohol to form an acylpalladium(II) species, which adds to phenylacetylene to generate an alkenylpalladium(II) intermediate. This intermediate undergoes further carbonylation and reductive elimination to produce the corresponding dicarbonylation product. For monocarbonylation, under basic conditions, the palladium catalyst reacts with phenylacetylene to form an alkynylpalladium(II) intermediate, which subsequently reacts with carbon monoxide and methanol to form a methoxyacylpalladium(II) species, followed by reductive elimination to yield methyl phenylacetylate and zero-valent palladium. The zero-valent palladium is directly oxidized by oxygen back to the palladium(II) catalyst, continuing the cycle. Their detailed elucidation of the reaction mechanism for heterogeneous catalysis provides important guidance for the design of heterogeneous catalysts.

In 2004, the Yamamoto group^[58] developed the palladium-phosphine catalyzed oxidative alkoxy-carbonylation of terminal alkynes, which proceeded with palladium chloride as the catalyst and triphenylphosphine as the ligand (Figure 6). This method has a broad scope, allowing not only alcohols but also amines to serve as nucleophiles to generate the corresponding 2-alkynamides. Initially, palladium chloride is reduced to zero-valent palladium, which is then oxidized by oxygen to form an (η₂-O₂)Pd(II) complex. Under the action of methanol, this complex generates an oxo-bridged Pd(II) dimer, which reacts with carbon monoxide to produce an acyl-Pd(II) species. Subsequently, this species exchanges with phenylacetylene in the presence of a base to form an acyloxy-alkynyl-Pd(II) intermediate, which undergoes reductive elimination to yield the product and zero-valent palladium. Further studies found^[59] that while triphenylphosphine participates in the carbonylation reaction, it can also be oxidized by oxygen to form triphenylphosphine oxide; however, its oxidation rate is slow and does not affect the normal course of the carbonylation reaction. The following year, they^[60] used the palladium-phosphine catalytic system to develop a tricarbonylation reaction involving terminal alkynes, where the products are obtained from mono-carbonylated 2-alkynoates through addition and carbonylation. However, due to the poor electrophilicity of the carbon-carbon triple bond in 2-alkynoates, the addition of the divalent palladium intermediate is difficult, leading to low conversion rates and poor selectivity in the tricarbonylation reaction.

In 2013, the Bhanage group^[61] achieved the oxidative alkoxycarbonylation of terminal alkynes using palladium/carbon as a catalyst and tetrabutylammonium iodide as a co-oxidant (Figure 7). Both aryl- and alkyl-substituted terminal alkynes were suitable for this reaction, yielding 2-alkynoates with good yields. The palladium catalyst was subjected to recycling tests, revealing that it maintained excellent catalytic activity even after the sixth cycle. Additionally, ICP-AES was used to detect the palladium content in the catalyst, and the results showed that there was virtually no loss of palladium in the catalyst after six cycles.

In 2016, the Muldoon group^[62] reported the palladium-amine catalyzed oxidative alkoxycarbonylation of terminal alkynes (Figure 8), where primary and secondary alcohols both showed excellent reactivity. They also applied this method to the post-modification of natural molecules, preparing a series of alkyne esters containing bioactive fragments, which provided a molecular library for the development of new drugs. In addition, the reaction used nitrogen gas containing 8% oxygen as the oxidant, making the conditions safer and greener, with good potential for research and industrial applications.

2-alkynamides, due to their unique structure and physiological activity, are widely present in drugs and bioactive molecules. There are mainly two synthetic methods. One is the direct amidation reaction of 2-alkynoic acids and their derivatives with amines, but the synthesis of 2-alkynoic acid derivatives is difficult, and some derivatives, such as acyl chlorides, have poor stability, leading to a limited range of 2-alkynamide structures prepared by this method. The other method involves the coupling of terminal alkynes with aminoacyl chlorides under metal catalysis. Although this method has a broader substrate scope, the poor stability of aminoacyl chlorides greatly reduces its practicality. Using terminal alkynes, amines, and carbon monoxide as raw materials, 2-alkynamides can be prepared through oxidative carbonylation, which has the advantages of wide availability of raw materials, simple operation, and high atom economy.

In 2001, Gabriele et al.^[63]reported the oxidative aminocarbonylation of terminal alkynes (see Figure 9). Using terminal alkynes as raw materials, 2-alkynamides were prepared through carbonylation with secondary amines such as diethylamine and morpholine under the catalysis of palladium iodide and potassium iodide. Both alkyl and aryl acetylenes could smoothly undergo the reaction. As shown in the mechanism, the terminal alkyne first reacts with palladium iodide to form an alkynylpalladium(II) species, which then undergoes carbonylation to produce an acylpalladium(II) species. This species further exchanges with the amine to generate an aminoacylpalladium(II) intermediate, which subsequently undergoes reductive elimination to yield the product and palladium(0). For the oxidation of palladium(0), iodide ions are first oxidized to elemental iodine under oxygen conditions, and the generated iodine serves as an oxidant to convert palladium(0) back to palladium(II) iodide, allowing the carbonylation cycle to continue. This method uses air to achieve the oxidation of the palladium catalyst, making it safer and more reliable than using pure oxygen, thus showing good prospects for industrial applications.

Bhanage et al.^[64⇓-66] have been dedicated to exploring ligand-free oxidative carbonylation reactions. In 2012, they^[67] reported the ligand-free oxidative aminocarbonylation of terminal alkynes using palladium/carbon as a catalyst (see Figure 10). Notably, the lone pair electrons of heteroatoms in heterocyclic compounds can easily coordinate with metals, leading to metal catalyst poisoning, and thus heterocyclic compounds generally show poor reactivity in metal-catalyzed reactions. Under these reaction conditions, heterocyclic compounds exhibited good reactivity, with alkyne substrates containing heterocyclic skeletons such as imidazole yielding the corresponding 2-alkynamides in excellent yields. Additionally, the palladium/carbon catalyst demonstrated good longevity, maintaining its catalytic efficiency and selectivity at a satisfactory level even after four cycles.

The Bhanage group^[68] developed an oxidative aminocarbonylation of tertiary amines in 2016 (Figure 11), using palladium on carbon as the catalyst and potassium iodide as the additive. Compared with the aforementioned work, it was found that when tertiary amines were used as substrates, the amount of catalyst required was lower. To elucidate the reaction mechanism of tertiary amines, the following experiments were conducted. Firstly, the corresponding aldehyde of the tertiary amine was detected in the reaction system, suggesting that during the reaction, the tertiary amine would lose one molecule of the aldehyde to form a secondary amine. Secondly, when the experiment was carried out under standard conditions without adding potassium iodide, almost no product was formed, proving the importance of potassium iodide in the reaction process. In summary, they proposed a reaction mechanism where palladium on carbon reacts with potassium iodide and oxygen to form palladium(II) iodide, which then reacts with the tertiary amine to generate an amino-palladium(II) species, releasing one molecule of aldehyde. Subsequently, the amino-palladium(II) undergoes carbonylation with carbon monoxide to form an acyl-palladium(II) intermediate, which then reacts with phenylacetylene via reductive elimination to produce the target 2-alkynamide and palladium(0). The palladium(0) is then re-oxidized by potassium iodide and oxygen to regenerate palladium(II) iodide. Both of these strategies for oxidative aminocarbonylation can be widely applied to the oxidative carbonylation of heterocyclic scaffolds, playing a significant role in enriching the library of 2-alkynamide molecules.

N-heterocyclic carbene ligands have received significant attention due to their strong σ-donor capability and high stability. To date, scientists have developed various metal/N-heterocyclic carbene complex-catalyzed organic reactions, such as cross-coupling reactions, asymmetric catalytic reactions, and olefin metathesis, etc.^{[69⇓⇓⇓⇓-74]}. In 2015, the Liu Jianhua research group^[75] applied the metal/N-heterocyclic carbene catalytic system to the field of oxidative carbonylation, reporting a palladium/N-heterocyclic carbene-catalyzed oxidative aminocarbonylation reaction (Figure 12). This catalytic system exhibited excellent performance with only 1% mol of catalyst required. Mechanistically, several key reaction intermediates, including amino-palladium(II) and acyl-palladium(II) species, were successfully captured using high-resolution mass spectrometry, based on which a reaction mechanism was proposed. The palladium catalyst first reacts with amine under basic conditions to form an amino-palladium(II) complex, which then undergoes carbonylation with carbon monoxide to produce an acyl-palladium(II) species. This species exchanges with alkyne under basic conditions to generate an alkynyl-acyl-palladium(II) intermediate, which undergoes reductive elimination to yield the target product and zero-valent palladium. Subsequently, the zero-valent palladium is oxidized by iodine to form divalent palladium, and the generated iodide ion is then oxidized back to iodine by oxygen, completing the oxidative cycle.

The following year, the Muldoon group^[76]reported a more efficient catalytic system for the carbonylation of oximes (Figure 13). The reaction was carried out with palladium acetate as the catalyst, tetramethylethylenediamine as the ligand, tetrabutylammonium iodide as the additive, and ethyl acetate as the solvent. In this, the amount of palladium acetate used was only 0.2 mol%. Typically, the oxidative carbonylation of terminal alkynes and amines uses 1,4-dioxane as the solvent to promote better dissolution of the metal catalyst in the reaction system. However, 1,4-dioxane has a low flash point and poor safety, which severely limits its application in the industrial field. By using tetrabutylammonium iodide as an additive, they successfully resolved the solubility issue of the catalyst, allowing the reaction to proceed in the highly stable solvent, ethyl acetate, thus greatly enhancing its feasibility for industrial applications. In terms of oxidation, the use of a mixture of oxygen and nitrogen as the oxidant significantly improved the safety.

In the field of heterogeneous catalysis, the Gabriele group^[77] utilized supported palladium catalysts to achieve the oxidative aminocarbonylation of terminal alkynes (see Figure 14). A novel solid-phase material, MWCNT-imi-X, was prepared by modifying multi-walled carbon nanotubes (MWCTs) with poly(ionic liquid). This material was then ion-exchanged with K₂PdI₄ to obtain the catalyst PdI₄@MWCNT-imi-X. This catalyst exhibited excellent performance in catalyzing the oxidative aminocarbonylation of various terminal alkynes. Moreover, after the reaction, the catalyst could be easily separated and recovered through simple filtration. Stability tests showed that the catalytic performance decreased slightly after four cycles. X-ray photoelectron spectroscopy revealed that as the number of cycles increased, the content of active center Pd(II) decreased while the proportion of inactive center Pd(0) increased. This experiment elucidated the reason for catalyst deactivation, providing a basis for the design of subsequent catalysts and reaction systems.

The Beller group^[78⇓-80] has been dedicated to the study of carbonylation reactions for a long time. In 2018, they reported^[81] the oxidative aminocarbonylation of primary amines. Unlike secondary and tertiary amines, primary amines ultimately yield dicarbonylated products, maleimides. GC-MS showed that no monocarbonylated product, 2-ynamide, was generated during the reaction. For this, they proposed a possible reaction mechanism. Firstly, palladium chloride reacts with amine and carbon monoxide to form an amido-palladium(II) species, which then adds to the terminal alkyne to form an alkenyl-palladium(II) species. The latter undergoes carbonyl insertion and ring closure to form a six-membered cyclic palladium(II) intermediate, which subsequently undergoes reductive elimination to produce maleimide and zero-valent palladium. Zero-valent palladium is oxidized back to palladium chloride under the action of oxygen and hydrogen chloride (Figure 15).

Tandem oxidative carbonylation-cyclization reactions of terminal alkynes can achieve the synthesis of highly functionalized heterocyclic compounds in one step, which is an efficient method. Given the importance of heterocyclic compounds in biologically active molecules, such methods can provide a rich and diverse library of heterocyclic molecules for the screening of biologically active molecules such as drugs.

In 1994, Gabriele et al.^[82] reported the oxidative carbonylation-cyclization reaction of terminal alkynes involving carbon monoxide and oxygen (Figure 16). Using 2,2-dimethyl propargyl alcohol as the substrate, under the catalysis of palladium iodide, it reacted with carbon monoxide and methanol to prepare 2-alkenyl-β-propiolactone. The reaction mechanism is shown in Figure 16. Palladium iodide first reacts with methanol and carbon monoxide to form acylpalladium (II), which then adds to the carbon-carbon triple bond in the propargyl alcohol to yield an alkenylpalladium (II) intermediate. This intermediate undergoes further carbonylation and reacts with the hydroxyl group of the propargyl alcohol to generate a five-membered ring palladium (II) species, which after reductive elimination produces the product and zero-valent palladium. The recycling of the palladium catalyst is accomplished by oxygen and iodine. Additionally, using homoallylic alcohol as the substrate can produce a series of 2-alkenyl-γ-butyrolactone compounds^[83]. The following year, the Gabriele group^[84] utilized a similar reaction strategy, with 2,2-disubstituted propargylamines as substrates, to develop a novel tandem oxidative aminocarbonylation-cyclization reaction for the selective synthesis of various four- and five-membered nitrogen-containing heterocyclic compounds. In 1999, Gabriele et al.^[85] used the aforementioned strategy to prepare furan-2-acetic acid methyl ester.

In 2004, Gabriele et al.^[86] reported an amine-involved tandem oxidative carbonylation-cyclization reaction (Figure 17). According to the previously reported ^[82] tandem carbonylation reaction of alcohol with 2,2-dimethyl propargyl alcohol, theoretically, the reaction involving amine should yield an amide-substituted β-propiolactone. However, it was found experimentally that the final product is a 4-amino-5H-furan-2-one compound. They proposed that the reaction between amine and propargyl alcohol follows a different reaction pathway. It is speculated that the basicity of the amine promotes the terminal alkyne to react with palladium iodide first, forming an alkynylpalladium(II) rather than the amine undergoing a carbonyl insertion reaction with palladium iodide to form an acylpalladium(II). After the formation of alkynylpalladium(II), it undergoes an aminocarbonylation reaction to generate an alkynamide, which is then added by another molecule of amine to form an eneamide intermediate. This intermediate undergoes intramolecular lactonization, releasing one molecule of amine, thus generating the target product. This method has a broad scope, as various substituted propargyl alcohols and amines can participate in the reaction, yielding 4-amino-5H-furan-2-ones in excellent yields.

Subsequently, they^[87]used propargylamine as the starting material to develop a water-involved four-component tandem oxidative carbonylation-cyclization reaction (Figure 18). First, under the catalysis of palladium iodide, propargylamine undergoes an aminocarbonylation reaction with carbon monoxide and a secondary amine to form a propargylic amide. The amino group in the propargylic amide then exchanges with palladium iodide to generate the corresponding amino-palladium(II), which further undergoes carbonylation to produce acyl-palladium(II). At this point, acyl-palladium(II) acts as a Lewis acid, coordinating with the carbon-carbon triple bond, enhancing its electrophilicity. Water, acting as a nucleophile, adds to the activated carbon-carbon triple bond, forming a six-membered ring palladium(II) intermediate, which subsequently undergoes reductive elimination to yield oxazolidinone and zero-valent palladium. Zero-valent palladium is oxidized back to palladium iodide by oxygen and potassium iodide, completing the catalyst cycle. Additionally, when the 1-position of the propargylamine is mono-substituted, the exocyclic double bond in the resulting oxazolidinone will undergo isomerization, ultimately leading to the more thermodynamically stable aromatic compound, oxazolone. In 2002, the Costa group^[88]achieved the efficient synthesis of oxazoline compounds under similar conditions using N-propargyl amides as the starting materials.

In 2001, Gabriele et al.^[89] developed a tandem oxidation carbonylation-cyclization reaction of 2-ethynylaniline, thereby constructing structurally complex dihydroindolone compounds in one step (Figure 19). This reaction exhibited excellent selectivity, yielding products with E-type double bonds exclusively. In terms of mechanistic studies, they used the oxidation amine carbonylation product, methyl 2-amino-phenylacetylate, as a starting material for the reaction, and ultimately did not obtain the target heterocyclic compound, thus ruling out the path where the terminal alkyne first undergoes an oxidative carbonylation reaction with carbon monoxide and amine. Based on this, two possible reaction mechanisms were proposed. Palladium iodide reacts with carbon monoxide and methanol to form an acylpalladium (II) complex, which then adds to the triple bond of 2-aminophenylacetylene to yield an enylpalladium (II) intermediate, followed by the reaction between the amino group and the ester group to form the intermediate 4a. Alternatively, palladium iodide could first undergo ion exchange with the amine group in the substrate to form an aminopalladium (II), which then undergoes carbonyl insertion with carbon monoxide to produce an acylpalladium (II) species; addition of this species to the carbon-carbon triple bond can also generate the intermediate 4a. After obtaining the intermediate 4a, isomerization of its double bond yields an E-type enylpalladium (II) compound, which then undergoes a carbonylation reaction with carbon monoxide and methanol to produce the target compound and zero-valent palladium; the latter is oxidized back to palladium iodide under the action of oxygen and potassium iodide, continuing the reaction cycle. Regarding the excellent stereo-selectivity of the product, Gabriele et al. believed that the Z-type enylpalladium (II) intermediate 4a is more stable than the E-type enylpalladium (II) intermediate, facilitating the rapid conversion of the Z-isomer into the E-isomer, thus leading to the stereospecific formation of (E)-3-(methoxycarbonyl)methylene-1,3-dihydroindol-2-one. Building on this work, they^[90] successfully prepared heterocyclic molecules containing an 8-membered lactam ring using 2-(2-ethynylphenoxy)aniline as the substrate.

In 2004, the Gabriele group^[91] reported the oxidative carbonylation-cyclization reaction of 4-pentyn-1-ol and secondary amines (Figure 20). This method can efficiently construct amide compounds with a tetrahydrofuran skeleton under mild conditions. During the experiment, it was found that when the reaction time was shortened, the formation of acetylenic amide 4b was detected. However, at the end of the reaction, no acetylenic amide 4b was obtained, thus it is speculated that acetylenic amide 4b is a key intermediate in the reaction. Based on this, a reaction mechanism was proposed. First, 4-pentyn-1-ol reacts with palladium iodide in the presence of a secondary amine to form an acetylenic palladium (II) intermediate, which then undergoes carbonylation to give an acyl palladium (II). The acyl palladium (II) undergoes ion exchange with the secondary amine, followed by reductive elimination to yield zero-valent palladium and acetylenic amide 4b. The latter undergoes intramolecular conjugate addition to form the tetrahydrofuran structure. Zero-valent palladium is then oxidized back to palladium iodide by oxygen and a combination of hydrogen iodide/potassium iodide, continuing to participate in the carbonylation reaction.

In 2018, they^[92] extended the above-mentioned tandem oxidative carbonylation-conjugate addition reaction to structurally complex substituted benzimidazoles (Figure 21). Using 1-propargyl-2-aminobenzimidazole and a secondary amine as substrates, amide compounds with a benzimidazole backbone were synthesized in one pot under palladium iodide catalysis. The TON value of this reaction's catalyst was high, with each mole of the catalyst producing 192~288 mol of the target product. To explore the reaction mechanism, they first prepared the ynolamide compound 4c and found that it could yield the target product under standard reaction conditions, proving that ynolamide 4c is an intermediate in the reaction. They proposed the following reaction mechanism: initially, the terminal alkyne forms a vinylpalladium (II) intermediate with palladium iodide, which then undergoes aminocarbonylation to produce ynolamide 4c. The amino group in 4c undergoes intramolecular conjugate addition with the ynolamide, yielding an eneamide compound, which spontaneously undergoes double bond isomerization to form a thermodynamically more stable aromatic polycyclic compound. This reaction provides a convenient and mild method for synthesizing a new class of benzimidazole molecules. Nitrogen-containing polycyclic heterocycles are structural fragments with physiological activity, and such novel molecular structures have significant implications for the development of new drugs. In 2020, they^[93] used the same reaction system to prepare heterocyclic compounds containing imidazopyridine structures, using 2-substituted aminopyridines as starting materials.

Oxycarbonylation, due to its excellent functional group tolerance, has broad application prospects in the total synthesis of complex natural molecules^[94]. In recent years, synthetic chemists have utilized terminal alkyne oxycarbonylation as a key step to report the total synthesis of various natural molecules. In 2007, the Jacobi group^[95] achieved the synthesis of the core skeleton of wortmannin through terminal alkyne oxidative alkoxy-carbonylation (Figure22). They used carbonate 5a as the starting material, obtaining the terminal alkyne compound 5b after six steps. The latter, under the catalysis of bis(triphenylphosphine)acetic acid palladium, underwent an oxidative alkoxy-carbonylation reaction with ethanol, yielding the acetylene ester compound 5c at a 70% yield. In compound 5c, the carbon-carbon triple bond and the oxazole undergo an intramolecular tandem Diels-Alder/retro-Diels-Alder reaction under heating conditions, removing acetonitrile to form the furan ring structure 5e. This structure was then further transformed to complete the construction of the wortmannin core skeleton.

In 2012, Jacobi et al.^[96] utilized a tandem Diels-Alder/retro-Diels-Alder reaction strategy to achieve the total synthesis of the viridin core skeleton (see Figure 23). The terminal alkyne compound 5f was prepared from 3,4-dihydrocoumarin through Friedel-Crafts reactions and 13 other steps. It then underwent oxidative ethoxycarbonylation with ethanol to form the ynoate 5g, with a yield of 78% for this step. The ynoate 5g underwent an intramolecular tandem Diels-Alder/retro-Diels-Alder under heating conditions, producing a compound 5h containing a furan skeleton, which was further processed via Mukaiyama aldol condensation and other reactions to prepare the core structure of viridin.

In 2016, the Snyder group^[97]used terminal alkyne oxidative carbonylation as a key step to complete the formal asymmetric synthesis of the akuammiline alkaloid Strictamine in just seven steps (Figure 24). First, the carboline derivative 5iunderwent an asymmetric propargylation to generate the carboline derivative 5jcontaining a terminal alkyne group, which then underwent oxidative methoxycarbonylation catalyzed by palladium acetate, yielding the enynyl ester 5kwith 80% yield. 5kwas then deprotected and subjected to intramolecular cyclization under Lewis acid catalysis to afford compound 5l. As reported by predecessors, 5lcan be converted into the akuammiline alkaloid Strictamine through two additional steps.

Since the oxidation carbonylation of terminal alkynes was reported, novel reactions and catalytic systems have been emerging continuously. Among them, carbon monoxide and oxygen, as the carbonyl source and oxidant respectively, have broad industrial application prospects due to their low cost and environmental friendliness. This paper introduces the recent progress in the oxidative carbonylation of terminal alkynes involving carbon monoxide and oxygen, discusses the oxidative carbonylation reactions of terminal alkynes mediated by different substrates, and focuses on elucidating the reaction mechanisms, including the carbonylation process and the oxidation process of the catalyst, aiming to help readers better understand the oxidative carbonylation reactions involving terminal alkynes.

Currently, although a large number of frontier works on the oxidative carbonylation of terminal alkynes have been reported, there is still a long way to go before industrialization. On one hand, the catalytic systems reported so far mainly focus on homogeneous reactions, which have the problem of difficult separation and reuse of catalysts. The few existing heterogeneous catalytic systems have low catalytic efficiency and short service life. Therefore, developing efficient and long-cycle-life heterogeneous catalysts is a key issue that needs to be addressed for the industrialization of the oxidative carbonylation of terminal alkynes. On the other hand, although oxygen is a green and environmentally friendly oxidant, its mixture with carbon monoxide poses a certain explosion risk. Developing new green and metal-catalyst-compatible oxidation systems is the best approach to solving the aforementioned safety issues. In addition, developing new oxidative carbonylation reactions of terminal alkynes to efficiently prepare structurally diverse unsaturated carbonyl compounds is also of great significance. With the in-depth study of oxidative carbonylation reactions, it is believed that more efficient and greener catalytic systems will be reported in the future, and the oxidative carbonylation of terminal alkynes will eventually successfully move towards industrialization.