Visible-Light-Catalyzed Regioselective Arylcarboxylation of Allenes with CO₂

Abstract

A visible-light-catalyzed arylcarboxylation of allenes with CO₂ was developed using [Ir(ppy)₂(dtbbpy)]PF₆ (ppy = 2-phenylpyridine; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine) as a photocatalyst to synthesis β-aryl β,γ-unsaturated carboxylic acids. This multicomponent protocol proceeds in an atom-economical way with exclusive regioselectivity. Preliminary mechanistic experiments suggested that allylic carbanion species are the key intermediates.

Key words

photocatalysis - allenes - arylcarboxylation - regioselectivity - carbon dioxide

As one of the largest classes of organic compounds, carboxylic acids play an important role, not only in organic synthesis, but also in biochemistry and medicinal chemistry, as many drugs and natural products contain a carboxylic acid group.[1] Therefore, it is of great significance to explore an efficient way to introduce carboxylic acid groups into organic compounds. Over the past few decades, many methods have been developed to synthesize carboxylic acids, among which the difunctionalization of unsaturated C–C bonds with CO₂ is one of the most direct, efficient, and atom-economical strategies.[2] However, due to the thermodynamic stability and kinetic inertness of CO₂, it is challenging to directly utilize CO₂ to construct carboxylic acids.

In recent years, visible-light-catalyzed reactions have played an increasingly important role in organic synthesis, and various photocatalytic reactions have emerged.[3] In this context, visible-light-catalyzed difunctionalization of unsaturated C–C bonds with CO₂ has attracted significant attention because it allows the simultaneous introduction of a carboxylic acid group and a second functional group, thereby representing a fascinating strategy for rapidly accessing functionalized carboxylic acids.[4] Although well documented for alkenes and alkynes,[5] visible-light-catalyzed difunctionalization of allenes with CO₂ has been largely undeveloped, and only a few examples have been reported. In 2021, Hong’s group developed a photoredox catalyzed aminoalkylcarboxylation of aryl allenes with CO₂ and N,N-dimethylanilines with moderate to excellent regioselectivity (Scheme [1a]).[6] Later, Yu’s group reported a visible-light-catalyzed dicarboxylation of allenes, with the incorporation of two CO₂ molecules (Scheme [1b]).[7] However, both methods suffer from selectivity issues and have poor regioselectivity for some allene substrates, which is a long-standing challenge in the functionalization of allenes. Most recently, our group developed a phosphonocarboxylation of allenes with diarylphosphine oxides and CO₂ through visible-light photoredox catalysis, with exclusive regio- and stereoselectivity (Scheme [1c]).[8] Nevertheless, photocatalyzed difunctionalizations of allenes with CO₂ are relatively rare and generally display poor selectivity. As a continuation of our work on photocatalyzed selective difunctionalization of unsaturated C–C bonds,[8] [9] we have developed the first visible-light-catalyzed arylcarboxylation of allenes with CO₂, delivering β-aryl β,γ-unsaturated carboxylic acids with complete regioselectivity. This strategy involves an efficient and atom-economical multicomponent reaction (Scheme [1d]).

Scheme 1 Previous and present work on photocatalyzed difunctionalization of allenes with CO₂

Table 1 Optimization of the Reaction Conditions^a

Entry	Variation in reaction conditions	Yieldb (%)
1	–	47
2	darkness	N.R.c
3	without PC	N.R.
4	without HCOONa	trace
5	without DABCO	trace
6	without K2CO3	trace
7	HCOOK instead of HCOONa	38
8	Na2CO3 instead of K2CO3	23
9	Cs2CO3 instead of K2CO3	32
10	t-BuOK instead of K2CO3	41
11	N2 instead of CO2	trace
12	Ir[dF(CF3)ppy]2(dtbbpy)PF6 as PCd	trace
13	fac-Ir(ppy)3 as PC	18

^a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2 equiv), [Ir(ppy)₂(dtbbpy)]PF₆ (5 mol%), DABCO (0.1 mmol, 0.5 equiv), K₂CO₃ (0.5 mmol, 2.5 equiv), HCOONa (0.4 mmol, 2 equiv), DMSO (2 mL), CO₂ (1 atm), r.t., 24 h, 20 W blue LED (450 nm).

^b Determined by ¹H NMR with 1,3,5-trimethoxybenzene as internal standard.

^c N.R. = no reaction.

^d dF(CF₃)ppy = 3,5-difluoro-2-[5-(trifluoromethyl)pyridine.

We began our investigation by employing 1,1-diphenylallene (1a) as the model substrate and iodobenzene (2a) as the arylation reagent with irradiation by a 20 W blue LED in the presence of commercially available [Ir(ppy)₂(dtbbpy)]PF₆ (ppy = 2-phenylpyridine; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine) as a photocatalyst (PC) under CO₂ at atmospheric pressure and ambient temperature for 24 hours (Table [1]). To our delight, the expected reaction proceeded smoothly, delivering the terminal carboxylation product 3a exclusively (Table [1], entry 1). The results of control experiments showed that none of the desired product was obtained in the absence of either light or the photocatalyst (entries 2 and 3). Notably, only a trace amount of the desired product was produced when DABCO, K₂CO₃, or HCOONa was omitted, indicating that all three are vital to this reaction (entries 4–6), and other alternatives proved to be less efficient (entries 7–10). Moreover, CO₂ was also shown to be essential for this transformation (entry 11). Our screening of photocatalysts revealed that [Ir(ppy)₂(dtbbpy)]PF₆ is the most suitable for the catalytic reaction (entries 12 and 13).

Scheme 2 Scope of the arylcarboxylation of allenes. Reaction conditions: 1 (0.2 mmol), 2 (2 equiv), [Ir(ppy)₂(dtbbpy)]PF₆ (5 mol%), DABCO (0.5 equiv), K₂CO₃ (2.5 equiv), HCOONa (2 equiv), DMSO (2 mL), CO₂ (1 atm), r.t., 24 h, 20 W blue LED (450 nm). Isolated yields are reported.

With the optimal reaction conditions in hand, we investigated the scope of the substrates for the reaction, and various allenes and aryl halides were tested. As shown in Scheme [2, 1],1-disubstituted allenes bearing various substituents were subjected to the visible-light-catalyzed arylcarboxylation with CO₂. The reaction proceeded efficiently in regioselective manner, producing the terminal carboxylation product exclusively. The main byproducts were allene polymerization products and hydroarylation products. Other byproducts were too complicated to analyze. Besides these, small amounts of the allene (0–10%) were recovered after the reaction. Symmetric 1,1-disubstituted allenes showed good compatibility toward this reaction, generating the corresponding arylcarboxylation product 3a–f in moderate yields. Notably, when the 1-aryl-1-alkylallenes were submitted to the standard reaction condition, high yields of the products were obtained with good selectivity toward the Z-products 3g–l; these are thermodynamically unstable, sterically hindered, and uncommon products for this type of reaction. Unsurprisingly, the reaction showed no Z/E selectivity when asymmetric 1,1-diarylallenes were used as the substrate (3m and 3n). Finally, preliminary studies were conducted to investigate the scope of the aryl iodide, and electron-withdrawing groups (carbonyl and cyano) were found to be tolerated in this reaction (3o and 3p).

Scheme 3 Preliminary mechanism studies and proposed mechanism

Concerning the mechanism, preliminary experiments were conducted to gain further insight into the nature of the allene arylcarboxylation. When five equivalents of a well-known radical scavenger (TEMPO or BHT) were added to the reaction mixture, the desired product was not observed, indicating this transformation might be a radical process (Scheme [3a]). Secondly, we performed isotope labeling studies with D₂O under a N₂ atmosphere (Scheme [3b]). We found a 78% deuterium incorporation at the terminal position of the hydroarylation product 3a′ when 50 equivalents of D₂O were added, indicating the formation of methyl allyl anion intermediate. On the basis of these mechanistic studies and previous works,[5a] we propose a possible mechanism for the reaction of visible-light-catalyzed arylcarboxylation of allenes with CO₂ and aryl halides. First, blue light (λ = 450 nm) irradiation promotes the single-electron transfer (SET) between the excited state of [Ir(ppy)₂(dtbbpy)]PF₆ and DABCO (HAT catalyst) to generate the corresponding DABCO radical cation A, which then traps the hydrogen of the formate salt and provides a CO₂ radical anion B. The aryl halide is then reduced by the radical anion B to afford the aryl radical C; this is followed by regioselective radical addition to the allene to afford an allylic radical intermediate D. A second SET between D and the reduced photocatalyst delivers an allylic carbanion intermediate E, which then undergoes nucleophilic addition to CO₂ to produce the target arylcarboxylation product.

In conclusion, we have developed the first highly regioselective strategy for the arylcarboxylation of allenes with CO₂ through visible-light photoredox catalysis to deliver β-aryl β,γ-unsaturated carboxylic acids,[10] which are widely present in pharmaceuticals. The methodology uses abundant and readily available CO₂ as the C₁ source and it represents an unprecedented example of a highly regioselective photocatalyzed arylcarboxylation of allenes.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

• 1a Gooßen LJ, Rodríguez N, Gooßen K. Angew. Chem. Int. Ed. 2008; 47: 3100
• 1b Majumdar N. ACS Catal. 2022; 12: 8291
• 2a Ran C.-K, Liao L.-L, Gao T.-Y, Gui Y.-Y, Yu D.-G. Curr. Opin. Green Sustainable Chem. 2021; 32: 100525
• 2b Ye J.-H, Ju T, Huang H, Liao L.-L, Yu D.-G. Acc. Chem. Res. 2021; 54: 2518
• 3 Romero NA, Nicewicz DA. Chem. Rev. 2016; 116: 10075

For selected examples and reviews of carboxylations using CO₂ as a C₁ source, see:
• 4a Cao G.-M, Hu X.-L, Liao L.-L, Yan S.-S, Song L, Chruma JJ, Gong L, Yu D.-G. Nat. Commun. 2021; 12: 3306
• 4b Ran C.-K, Xiao H.-Z, Liao L.-L, Ju T, Zhang W, Yu D.-G. Natl. Sci. Open 2023; 2: 20220024 ; DOI:
• 4c Lan J, Lu X, Ren B, Duo F, Niu X, Si J. Org. Biomol. Chem. 2024; 22: 682
• 4d Zhang W, Chen Z, Jiang YX, Liao LL, Wang W, Ye JH, Yu DG. Nat. Commun. 2023; 14: 3529
• 5a Wang H, Gao Y, Zhou C, Li G. J. Am. Chem. Soc. 2020; 142: 8122
• 5b Hou J, Ee A, Cao H, Ong HW, Xu JH, Wu J. Angew. Chem. Int. Ed. 2018; 57: 17220
• 5c Yin Z.-B, Ye J.-H, Zhou W.-J, Zhang Y.-H, Ding L, Gui Y.-Y, Yan S.-S, Li J, Yu D.-G. Org. Lett. 2018; 20: 190
• 5d Ye J.-H, Miao M, Huang H, Yan S.-S, Yin Z.-B, Zhou W.-J, Yu D.-G. Angew. Chem. Int. Ed. 2017; 56: 15416
• 6 Hahm H, Baek D, Kim D, Park S, Ryoo JY, Hong S. Org. Lett. 2021; 23: 3879
• 7 Ju T, Zhou Y.-Q, Cao K.-G, Fu Q, Ye J.-H, Sun G.-Q, Liu X.-F, Chen L, Liao L.-L, Yu D.-G. Nat. Catal. 2021; 4: 304
• 8 Zeng J.-H, Du D.-T, Liu B.-E, Zhang Z.-Q, Zhan Z.-P. J. Org. Chem. 2023; 88: 14789
• 9 Gao C, Zeng J, Zhang X, Liu Y, Zhan Z.-p. Org. Lett. 2023; 25: 3146
• 10 Photocatalyzed Arylcarboxylation of Allenes with CO₂: General Procedure An oven-dried 10 mL Schlenk tube equipped with a magnetic stirrer bar was charged with the appropriate allene 1 (0.2 mmol, 1 equiv, if solid), DABCO (0.1 mmol, 0.5 equiv), K₂CO₃ (0.5 mmol, 2.5 equiv), HCOONa (0.4 mmol, 2 equiv), and Ir[(ppy)₂dtbbpy]PF₆ (5 mol%). The tube was sealed and degassed by three cycles of vacuum evacuation and subsequent backfilling with CO₂. Subsequently, the appropriate allene 1 (0.2 mmol, 1 equiv, if liquid), the appropriate aryl iodide 2 (0.4 mmol, 2 equiv), and anhyd DMSO (2 mL) were added. The tube was placed under a blue LED (λ = 450 nm, 20 W) and irradiated for 24 h at r.t. The mixture was then acidified with 2 N aq HCl (1 mL) and quenched with H₂O. It was then extracted with EtOAc (×3) and the combined organic layers were dried (MgSO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, hexane–EtOAc (5:1 to 1:1)] or by preparative TLC (hexane–EtOAc, 1:1). 3,4,4-Triphenylbut-3-enoic acid (3a) Prepared by following the general procedure and purified by column chromatography [silica gel, hexane–EtOAc (3:1)] to give a white solid; yield: 27 mg (43%). ¹H NMR (400 MHz, CDCl₃): δ = 7.38–7.27 (m, 5 H), 7.19–7.10 (m, 5 H), 7.09–6.99 (m, 3 H), 6.96–6.88 (m, 2 H), 3.58 (s, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 177.23, 143.75, 142.66, 142.21, 141.36, 131.80, 130.75, 129.80, 129.52, 128.58, 128.10, 127.64, 127.42, 126.87, 126.50, 41.57. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₁₉O₂: 315.1380; found: 315.1382.

Publication History

Received: 12 March 2024

Accepted after revision: 22 March 2024

Accepted Manuscript online:
22 March 2024

Article published online:
09 April 2024