Metallaphotoredox-catalyzed alkynylcarboxylation of alkenes with CO₂ and alkynes for expedient access to β-alkynyl acids

Abstract

Carboxylation with CO₂ offers an attractive and sustainable access to valuable carboxylic acids. Among these methods, direct C−H carboxylation of terminal alkynes with CO₂ has attracted much attention for one-carbon homologation of alkynes, enabling rapid synthesis of propiolic acids. In contrast, the multi-carbons homologation of alkynes with CO₂ to construct important non-conjugated alkynyl-containing acids has not been reported. Herein, we present alkynylcarboxylation of alkenes with CO₂ via photoredox and copper dual catalysis. This protocol provides a direct and practical method to form valuable non-conjugated alkynyl acids from readily available alkynes, alkenes and CO₂. Additionally, this approach also features mild (room temperature, 1 atm of CO₂) and redox-neutral conditions, high atom and step economy, good functional group tolerance, and high selectivities. Moreover, diverse transformations of the β-alkynyl acid products and the rapid synthesis of bioactive molecule (GPR40/FFA1 agonist) further illustrate the synthetic utility of this methodology.

The report for the multi-carbon homologation of alkynes with CO₂ to construct important non-conjugated alkynyl-containing acids is rare. Herein, the authors report alkynylcarboxylation of alkenes with CO₂ via photoredox and copper dual catalysis, affording non-conjugated alkynyl acids from readily available alkynes, alkenes and CO₂.

Introduction

Carbon dioxide (CO₂) is an ideal one-carbon source due to its abundance, easy availability and non-toxicity. Consequently, the conversion of CO₂ into high-value-added chemicals has recently garnered significant attention^1–4. Notably, carboxylation with CO₂ has emerged as an effective method to synthesize diverse carboxylic acids, which are not only widely found in various bioactive molecules but also serve as versatile synthetic building blocks in modern organic synthesis^5–10. So far, various kinds of carboxylation reactions of (pseudo)organohalides^11–14, carbonyl compounds¹⁵, alkenes^16–23, alkynes^24–27, arenes^28–31, and other hydrocarbons^32–34 have been developed. Among them, the direct C−H carboxylation of alkynes with CO₂ has been extensively studied for the homologation of alkynes^35,36, which can rapidly and efficiently produce high-value propiolic acids³⁷. Despite significant progress, existing carboxylation reactions of alkynes remain limited to one-carbon homologation of alkynes via C(sp)−CO₂H bonds formation (Fig. 1a, left). In contrast, the multi-carbons homologation of alkynes with CO₂ (Fig. 1a, right), which is highly desirable to construct unaccessible and important non-conjugated alkynyl-containing acids, has not been reported, perhaps due to the easily occurring C−H carboxylation of alkynes with CO₂ as side reaction. Considering the significant utility of non-conjugated alkynyl-containing acids in both synthetic and medicinal chemistry^38–44 (Fig. 2), the development of a new strategy for the multi-carbons homologation of alkynes with CO₂ is a highly rewarding goal.

Fig. 1. Access to alkynyl-containing carboxylic acids via carboxylation of alkynes with CO₂.

a Access to alkynyl-containing acids via carboxylation of alkynes with CO₂. b Our design: metallaphotoredox-catalyzed multi-carbons homologation of alkynes with CO₂. c This work: three-component carboxylation for access to β-alkynyl acids via photoredox/copper dual catalysis.

Fig. 2. Representative bioactive molecules.

Selected examples of bioactive molecules and pharmaceuticals featuring β-alkynyl acid motifs.

Recently, photoredox catalysis has emerged as a powerful tool in organic chemistry^45–47, enabling a series of challenging reactions under mild conditions. Notably, the merger of photoredox catalysis with transition metal catalysis further expands the catalytic paradigm of synthetic methodology^48–50. Accordingly, the use of metallaphotoredox catalytic systems to achieve carboxylations with CO₂ has garnered increasing attention in recent years^51–55. Nevertheless, the existing metallaphotoredox system has not been employed to realize multi-carbons homologation of alkynes with CO₂ for the synthesis of non-conjugated alkynyl-containing acids. To address such a problem, we aim to develop a metallaphotoredox catalytic system to achieve the three-component coupling reaction of terminal alkynes, alkenes, and CO₂. The conversion of alkenes into active radical anion intermediates with two reaction sites and the selective recognition of alkynes and CO₂ via synergistic catalysis may represent a crucial step in achieving this objective. Based on the advantages of copper-catalyzed radical alkynylation reactions^56–60 and our research accumulation in the field of CO₂ conversion^6,10, a photoredox/copper synergistic catalytic strategy is designed. We hypothesized the in-situ generation of alkene radical anion species through photocatalytic single-electron transfer (SET) reduction and following nucleophilic attack on CO₂ would yield carboxylated alkyl carbon radicals. Subsequently, the generated free carbon radicals would undergo copper-catalyzed C(sp)−C(sp³) bonds formation, thereby generating non-conjugated alkynyl carboxylic acids (Fig. 1b). The establishment of this methodology could facilitate multi-carbons homologation of alkynes with CO₂, resulting in the efficient synthesis of important β-alkynyl acids. However, several challenges may impede success. First, the copper-catalyzed direct C−H bond carboxylation of terminal alkynes with CO₂ is highly efficient and thus competitive to the desired process^35,36. Second, the competitive hydrocarboxylation¹⁶, dicarboxylation²⁰, polymerization/oligmerization⁶¹ of alkenes and alkynes^24,27 may also occur, further complicating the reaction mixture. Third, the oxidative homocoupling of terminal alkynes in the presence of copper catalysts can also easily take place^62,63. Herein, we report alkynylcarboxylation of alkenes with CO₂ via photoredox and copper dual catalysis (Fig. 1c). This synergistic catalytic strategy offers an effective approach to valuable β-alkynyl acids from simple and readily available feedstocks. This reaction features mild and redox-neutral conditions, high atom-, step- and redox economy, and good functional group tolerance. The practicality of this methodology is demonstrated through both a scale-up reaction and abundant transformation of the β-alkynyl acid products, as well as the rapid synthesis of an important potential antidiabetic agent.

Results

Screening of reaction conditions

We began our investigations by evaluating the alkynylcarboxylation reaction of styrene 1a with cyclopropyl acetylene 2a under an atmosphere of CO₂ (Table 1). After systematical investigation, the desired β-alkynyl carboxylic acid 3aa was obtained in 84% isolated yield when using 5,10-diphenyldihydrophenazine (PAZ) as the photocatalyst, CuCl as the metal catalyst and KO^tBu as the base in dimethyl sulfoxide (DMSO) under 395 nm LED irradiation (entry 1). Other commonly used photocatalysts, such as 10-phenyl-10H-phenothiazine (PTH), 1,2,3,5-tetrakis(carbazol-9-yl)−4,6-dicyanobenzene (4CzIPN), fac-Ir(ppy)₃ and 10-phenyl-10H-phenoxazine (PXZ), were found to be ineffective for this reaction (entries 2-5). The binaphthol photocatalysts also exhibited good reactivity, generating 3aa in slightly lower yields (entries 6-7). The use of other copper catalysts, bases and solvents all resulted in lower yields (entries 8-12, see Supplementary Table. 1 in Supplementary Information (SI) for more details). The reaction carried out with a reduced copper catalyst loading could still afford 3aa in 78% yield (entry 13). Control experiments revealed that CO₂, light irradiation, photocatalyst and copper catalyst were all crucial to this transformation (entries 14−17). In addition, KO^tBu was also important for this alkynylcarboxylation reaction to achieve a high yield (entry 18).

Table. 1.

Optimization of the reaction conditions^a

Entry	Variation from standard conditions	Yield of 3aa (%)b
1	none	86 (84)
2	PTH instead of PAZ	N.D.
3	PXZ instead of PAZ	N.D.
4c	4CzIPN instead of PAZ	N.D.
5c	fac-Ir(ppy)3 instead of PAZ	N.D.
6c	BINOL instead of PAZ	79
7c	3,3’,6,6’-tBu4-BINOL instead of PAZ	65
8	CuCl2 instead of CuCl	60
9	CuBr instead of CuCl	72
10	CuOAc instead of CuCl	78
11	K2CO3 instead of KOtBu	62
12	DMF instead of DMSO	65
13	15 mol% CuCl	78
14	N2 instead of CO2	N.D.
15	w/o light	N.D.
16	w/o CuCl	N.D.
17	w/o PAZ	N.D.
18	w/o KOtBu	32

^aReaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), PAZ (1 mol%), CuCl (20 mol%), KO^tBu (0.6 mmol), DMSO (3 mL), CO₂ (1 atm), 30 W 395 nm LED, room temperature (rt), 24 h, then MeI (0.8 mmol), 65 °C, 4 h. ^bYields were determined by ¹H NMR using 1,3,5-trimethoxybenzene as an internal standard. Isolated yield in parentheses. ^cUnder 30 W 450 nm LED irradiation. LED light-emitting diode, N.D. not detected, ppy 2-phenylpyridine, Cz carbazole, BINOL 1,1’-bi-2-naphthol, DMF N,N-dimethylformamide, w/o without.

Substrate scope

With the optimized reaction conditions established, we first sought to determine the scope of terminal alkynes. As shown in Fig. 3, a broad range of alkyl terminal alkynes performed well in the reaction with styrene 1a and CO₂, affording the desired β-alkynyl carboxylic acids with moderate-to-good yields. Terminal alkynes bearing various kinds of cycloalkyl chains, such as cyclopropyl (3aa), cyclohexyl (3ab), tetrahydropyranyl (3ac) and N-Boc piperidyl (3ad), were compatible in this reaction to provide the corresponding products in good yields. It is worth noting that the chain length did not significantly affect the reactivity of the terminal alkynes (3ae and 3af). Moreover, a variety of reactive functional groups, including ether (3ac, 3ag and 3ah), Boc (3ad), ester (3ai, 3ak and 3al) and amide (3aj), were tolerated well in this method. Notably, the terminal alkynes derived from bioactive molecules, such as menthol (3ak) and isoborneol (3al), were applicable in this protocol. Significantly, some heteroaryl substituted substrates, such as thiophene (3am), pyrrole (3an) and carbazole (3ao), also reacted smoothly to afford the desired products in good yields. In addition, the alkyne with large steric hindrance (3ap) was a suitable substrate. Besides alkyl alkynes, aryl alkyne (3aq) and heteroaryl alkyne (3ar) can also participate in the alkynylcarboxylation reaction to deliver the products in synthetically useful yields. To our delight, the silyl-protected terminal alkynes underwent the reaction smoothly to generate the corresponding β-alkynyl acids (3as and 3at), providing opportunities for diverse downstream chemistry.

Fig. 3. The substrate scope of alkynes and alkenes.

a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), PAZ (1 mol%), CuCl (20 mol%), KO^tBu (0.6 mmol), DMSO (3 mL), CO₂ (1 atm), 30 W 395 nm LED, rt, 24 h; yields of isolated methyl esters or carboxylic acids are provided. b K₂CO₃ (0.6 mmol) and DMF (3 mL) were used. c KO^tBu (4.0 equiv) was used. d Diastereomeric ratio was determined via crude ¹H NMR analysis. Boc tert-butyloxycarbonyl, TBS tert-butyldimethylsilyl, TIPS triisopropylsilyl.

We then investigated the reactivity of various alkenes. As shown in Fig. 3, diverse substituted styrenes 1 with electron-neutral, electron-donating or electron-withdrawing groups on the aromatic ring could undergo the reaction smoothly, resulting in the desired products in moderate-to-good yields. Notably, a wide range of useful functional groups were well tolerated, including ether (3ca, 3ja-3ma and 3oa), Boc (3da and 3pa), fluoro (3fa and 3ma), carboxyl (3ga), chloro (3 ha) and cyano (3ia). In addition, the substrates bearing either unactivated alkene (3ja) or internal alkyne (3ka) moieties also underwent the reaction smoothly, generating the desired products with high selectivity. Unfortunately, no corresponding acid products were observed for styrenes bearing amino, hydroxyl and bromo groups (see Supplementary Fig. 2 for more details). Disubstituted aryl alkenes (3la and 3ma) were suitable substrates. Importantly, styrenes bearing naphthalenes (3na and 3oa) and heteroaromatic alkenes, such as indole (3pa), benzothiophene (3qa), pyrazole (3ra) and benzofuran (3sa) moieties, which are prevalent motifs in medicinal chemistry, were applicable in the reaction. To our delight, the internal alkene (3ta) proved to be a competent substrate, providing the corresponding product in a 58% yield. Besides, an electron-deficient acrylamide (3ua) also afforded the desired product, albeit with a low yield. The detection of byproduct from this reaction further demonstrated that C(sp)−H carboxylation is the primary side reaction, which reduced yields in certain cases. (see Supplementary Fig. 1 for more details).

Synthetic applications

To highlight the synthetic utility of this method, we conducted the following transformations. Initially, a gram-scale reaction of 1a and 2a was carried out, providing the product 3aa in 86% yield (Fig. 4a). Notably, the resulting β-alkynyl carboxylic acid could undergo further intramolecular cyclization in-situ in the presence of water, delivering the γ-lactone product 4aa in good yield (Fig. 4b)⁶⁴. Then, we explored divergent transformations of β-alkynyl carboxylic acid products (Fig. 4c). Product 3aq could be smoothly converted to allene 5 in a 77% yield via base-catalyzed isomerization⁶⁵. Starting from methyl ester 3aa, the corresponding product amide 6 and alcohol 7 can be obtained in 78% and 72% yields through the ammonolysis and reduction of methoxycarbonyl^66,67. The silyl from β-alkynyl carboxylic acid 3as could be readily removed in the presence of TBAF to access terminal alkyne 8 in excellent yield, which could be further converted into 1,2,3-triazole 9 in excellent yield via click reaction⁶⁸. Moreover, the Au-catalyzed intramolecular cycloisomerization of β-acetenyl acids 8 afforded γ-lactone 10 in an excellent yield⁶⁹. In addition, lactone 11 containing an alkenyl iodide was also obtained in 69% yield from 8 by halolactonization using NIS⁷⁰. These outcomes demonstrated that β-alkynyl acids are amenable to a variety of valuable transformations, thus reinforcing the potential application of this methodology in the construction of intricate carboxylic acid derivatives. More importantly, the application of this protocol in the concise synthesis of a pharmaceutically active molecule was eventually studied. β-alkynyl acid 14 is an extensively studied GPR40/FFA1 agonist with significant potential for the treatment of type 2 diabetes³⁸. The alkynylcarboxylation of 1d with propyne 2u followed by one-pot deprotection afforded key intermediate 12 in a 44% yield. Subsequently, a base-mediated phenol alkylation of 12 with benzyl bromide derivative 13 occurred efficiently to give FFA1 agonist 14 in a 93% yield (Fig. 4d).

Fig. 4. Synthetic applications.

a Gram-scale reaction. b In-situ cyclization reaction. c Post-functionalization of product. Reaction conditions: (a) 3aq (1.0 equiv), TBD (0.2 equiv), THF (6 mL), N₂, rt, 48 h, Ar = 4-Me-C₆H₄; (b) 3aa (1.0 equiv), MeNH₂ (33 wt% in EtOH), rt-60 °C, 48 h; (c) 3aa (1.0 equiv), LiBH₄ (2.0 M in THF, 4.0 equiv), Et₂O, N₂, rt, 7 h; (d) 3as (1.0 equiv), TBAF (1 M in THF), THF, 80 °C, 8 h, then 2 N HCl; (e) 7 (1.0 equiv), CuTc (0.1 equiv), TsN₃ (1.0 equiv), toluene, N₂, rt, 4 h; (f) 7 (1.0 equiv), AuCl₃ (2.5 mol%), toluene:H₂O = 1:1, rt, 16 h; (g) 7 (1.0 equiv), NIS (2.0 equiv), KHCO₃ (2.0 equiv), ⁿBu₄NOH (1 M in MeOH), DCM, rt, 30 min; (h) 12 (1.0 equiv), 3-(bromomethyl)−4’-(trifluoromethyl)−1,1’-biphenyl 13 (1.0 equiv), ⁿBu₄POH (40 wt% in H₂O, 2.05 equiv), THF, −5 °C, 0.5 h, then rt, 16 h. d Synthesis of bioactive molecule. TBD triazabicyclodecene, THF tetrahydrofuran, TBAF tetrabutylammonium fluoride, CuTc copper(I)thiophene-2-carboxylate, NIS N-iodosuccinimide.

Mechanistic studies

To gain insights into the reaction mechanism, some experiments were performed as shown in Fig. 5. First, time-resolved luminescence quenching experiments were conducted with different concentrations of 1a (Fig. 5a). The excited state lifetime of the photocatalyst PAZ decreases linearly with the increase of substrate 1a concentration, indicating that a SET process between the excited PAZ and 1a may occurr. Second, the alkynylcarboxylation reaction was completely suppressed when a stoichiometric amount of the radical scavengers 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO) or PhSeSePh was added to the reaction mixture. In addition, the possible alkyl-TEMPO adduct 15 was detected by high-resolution mass spectrometry (HRMS) (Fig. 5b), indicating that benzylic radicals may be involved in this transformation. When 1 equivalent of copper acetylide 2q’ was added to the system in the absence of alkyne 2q and CuCl, the product 3aq’ was obtained smoothly in 36% yield (Fig. 5c). This result suggests the copper acetylide may be generated as a key intermediate. Furthermore, no product 3aa’ was detected when cinnamic acid 16 was used instead of styrene under standard conditions, indicating that the C(sp)−C(sp³) bond was not formed through a Michael-type addition pathway (Fig. 5d).

Fig. 5. Mechanistic investigations.

a Time-resolved luminescence quenching experiments. b Control experiments with radical scavengers. c Investigation of copper acetylide intermediate. d Attempted study of the possible pathway via Michael addition.

Based on the above preliminary results and previous studies^21,22, a plausible mechanism is proposed as shown in Fig. 6. Upon irradiation of purple light, photocatalyst PAZ is initially excited to its excited state PAZ*, which then undergoes the SET process with alkene 1 to give the corresponding alkene radical anion I^{20–22,71–74} and PAZ radical cation. Subsequently, the nucleophilic addition of alkene radical anion I to CO₂ produces the carboxylated benzyl radical II. Meanwhile, copper(I) acetylide intermediate III is formed by deprotonation of the terminal alkyne in the presence of base and Cu(I) salt, followed by a SET process with PAZ radical cation to generate Cu(II) complex IV. Finally, the interaction of Cu(II) complex IV and alkyl radical II affords the desired product V and regenerates the Cu(I) catalyst for the next catalytic cycle^56–60. At this stage, we could not exclude other possible pathways and are still investigating on the reaction pathways.

Fig. 6. A possible mechanism.

Proposed dual catalytic cycle for alkynylcarboxylation of alkenes with CO₂.

Discussion

In summary, we have developed alkynylcarboxylation of alkenes with terminal alkynes and CO₂ via photoredox/copper dual catalysis, which provides expedient access to β-alkynyl carboxylic acids in good yields under mild and redox-neutral conditions. In addition, the alkynylation products can be readily transformed into synthetically useful building blocks. Furthermore, the potential antidiabetic agent (GPR40/FFA1 agonist) has been efficiently synthesized from commercially available raw materials in a two-step process using this strategy. Further applications based on metallaphotoredox catalysis are still ongoing in our laboratory.

Methods

In order to facilitate the purification of products, two distinct workup methods (methylation and acidification) will be selectively employed. Our study indicated that there was no significant difference in yield between the two methods.

General procedure A for the synthesis of methyl carboxylate

The oven-dried 10 mL sealed tube equipped with a magnetic stir bar was charged with 1 (0.2 mmol, 1.0 equiv, if solid), 2 (0.3 mmol, 1.5 equiv, if solid), PAZ (0.7 mg, 0.002 mmol, 0.01 equiv) and transferred to the glovebox. Then KO^tBu (67.3 mg, 0.6 mmol, 3.0 equiv) and CuCl (4.0 mg, 0.04 mmol, 0.2 equiv) were added. The tube was sealed and removed from the glovebox, then evacuated and back-filled with CO₂ atmosphere three times. Anhydrous DMSO (3 mL), 1 (if liquid) and 2 (if liquid) were added under CO₂ flow and the tube was sealed at atmospheric pressure of CO₂ (1 atm). The reaction mixture was irradiated with a 30 W purple LED (395 nm) and stirred in water bath at rt for 24 h. Upon completion of the reaction, MeI (0.8 mmol, 50 μL, 4.0 equiv) was added, the mixture was stirred at 65 °C for 4 h and then cooled to room temperature. The resulting mixture was diluted with H₂O and then extracted by EtOAc with three times. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc 100/1 ~ 10/1) to afford the pure desired product.

General procedure B for the synthesis of carboxylic acid

The oven-dried 10 mL sealed tube equipped with a magnetic stir bar was charged with 1 (0.2 mmol, 1.0 equiv, if solid), 2 (0.3 mmol, 1.5 equiv, if solid), PAZ (0.7 mg, 0.002 mmol, 0.01 equiv) and transferred to the glovebox. Then KO^tBu (67.3 mg, 0.6 mmol, 3.0 equiv) and CuCl (4.0 mg, 0.04 mmol, 0.2 equiv) were added. The tube was sealed and removed from the glovebox, then evacuated and back-filled with CO₂ atmosphere three times. Anhydrous DMSO (3 mL), 1 (if liquid) and 2 (if liquid) were added under CO₂ flow and the tube was sealed at atmospheric pressure of CO₂ (1 atm). The reaction mixture was irradiated with a 30 W purple LED (395 nm) and stirred in water bath at rt for 24 h. Then, the reaction mixture was diluted with 3 mL of EtOAc and quenched by 3 mL of 2 N HCl (aq.) and then stirred for 2 min. The resulting mixture was diluted with H₂O and then extracted by EtOAc with three times. The combined organic phases were concentrated in vacuo and the residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc 10/1 ~ 5/1, then 0.2% AcOH in petroleum ether/EtOAc 5/1 ~ 2/1) to afford the pure desired product.

Author contributions

J.C.X., J.P.Y., W.Z., and D.G.Y. conceived and designed the study. J.C.X., J.P.Y., M.P., Y.C.C., W.W., and X.Z. performed the experiments and mechanistic studies. J.C.X., J.P.Y., W.Z., J.H.Y., and D.G.Y. wrote the paper. All authors contributed to the analysis and interpretation of the data.

Peer review

Peer review information

Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Data availability

The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information files. Extra data are available from the corresponding author upon request.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-025-57060-w.