Dual nickel/photoredox catalyzed carboxylation of C(sp²)-halides with formate

Abstract

Herein, we report an efficient and practical protocol for dehalocarboxylation of C(sp²)-halides with formate by the engagement of a CO₂ radical anion in a nickel-mediated bond-forming process. A wide variety of aryl iodides, aryl bromides, and alkenyl bromides bearing a diverse set of functional groups underwent the reaction smoothly through visible-light photoredox nickel dual catalysis. The synthesis of several ¹³C-labeled drug intermediates and the gram-scale synthesis of commercial drugs highlight the synthetic value of the approach in drug discovery settings.

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Introduction

Aromatic carboxylic acids represent a class of important structural motifs that are widespread in numerous drug molecules, natural products, and useful synthetic intermediates (Scheme 1a).¹ Palladium-catalyzed carbonylation of aryl halides using carbon monoxide (CO) gas represents an efficient and straightforward approach to synthesize these compounds.² However, difficulties in handling this highly toxic gas limit its applications in medicinal chemistry research and complex organic syntheses. To circumvent these issues, efforts have been made in the past decades to develop CO-gas-free carbonylation of aryl halides.³ Among the various CO surrogates, formic acid, a renewable green C1-building block that can be obtained through hydrolyzation/oxidation of biomass and hydrogenation of CO₂,⁴ presents an easily operational CO source with a high weight percentage of CO. Many research groups, such as Skrydstrup,⁵ Shi,⁶ Wu,⁷ Zhou,⁸ and others,⁹ have developed a series of efficient carbonylation reactions through a thermal pathway using formic acid and its salts. While these efforts have significantly expanded the set of tools available for carbonylation of aryl halides (Scheme 1b), the requirement for precious palladium salts as catalysts, a stoichiometric amount of activator, and heating conditions limits its wide application on a large scale. Therefore, the development of a mild and sustainable protocol to synthesize arene carboxylic acids from aryl halides using formic acid and its salts is still a highly rewarding goal.

Scheme 1 Carboxylation of aryl halides with formate for the synthesis of aryl carboxylic acids.

In recent years, visible-light photoredox catalysis has emerged as a powerful tool for chemists¹⁰ because of its potential to allow the access to reactive intermediates that are unavailable to conventional thermal pathways, via single-electron-transfer (SET) and energy-transfer processes under mild reaction conditions. Moreover, the rapid development of photocatalysis has also brought new impetus for studies on the use of formate for the formation of the carbon dioxide radical anion (CO₂˙⁻),¹¹ which has shown broad utility as a reactive intermediate in organic synthesis.¹² In particular, the groups of Jui¹³ and Wickens¹⁴ recently reported elegant photochemical processes to synthesize carboxylic acids from the reaction of formate with activated alkenes without the need for a sacrificial electron donor, in contrast to CO₂-reduction strategies. Nevertheless, these types of reactions, which involve the participation of the CO₂ radical anion, are limited to radical addition to unsaturated substrates or to radical–radical couplings. The synergistic merging of photoredox catalysis and transition-metal catalysis (termed metallaphotoredox catalysis) resulted in many new discoveries that were unfeasible or difficult to achieve with a single catalytic system in recent years.¹⁵ To the best of our knowledge, however, the use of a metallaphotoredox strategy to promote formate as a CO₂ radical anion for C–C bond formation reactions has not been realized to date. Inspired by these pioneering works^11–14 and continuing our interest in photoredox catalysis¹⁶ and carboxylation reactions,^9a,17 we questioned whether merging visible-light photoredox with nickel catalysis might be used to realize the carboxylation of aryl halides with formate through a CO₂ radical anion intermediate (Scheme 1c).

The mechanistic details of our proposed dual nickel/photoredox catalyzed carboxylation of aryl halides with formate are outlined in Scheme 2. The formate salt can be oxidized to the radical intermediate by the excited photocatalyst,^13,14,18 which then undergoes a hydrogen atom transfer process upon oxidation to deliver formic acid and the CO₂ radical anion. It should be noted that the CO₂ radical anion has a very negative reduction potential (E_1/2 = −2.2 V vs. SCE), which is enough to reduce aryl chlorides smoothly.^11c,d At this stage, we hoped that the CO₂ radical anion would be rapidly captured by L_n–Ni(0) species A rather than the aryl halide getting reduced by it, to generate the intermediate B (path a). Subsequent oxidative addition of the aryl halide with Ni(I) species B generates the key Ni(III) intermediate C. Alternatively, a catalytic pathway is also plausible involving the oxidative addition of aryl halides with Ni(0) species A to give Ni(II) species E, which is trapped by the CO₂ radical anion to provide the same Ni(III) intermediate C (path b). The high-valent Ni(III) species C undergoes a facile reductive elimination to give the desired product and Ni(I) complex D. Reduction of Ni(I) complex D by the highly reducing catalyst species regenerates the Ni(0) species and [PC] to close the two catalytic cycles. Simultaneously, the competing dehalogenation reduction of aryl halides by formate under visible-light irradiation is a challenge for the smooth occurrence of the proposed reaction (path c).

Scheme 2 Envisioned catalytic cycle.

Results and discussion

We examined the feasibility of this proposed metallaphotoredox dehalocarboxylation protocol with 4-iodobiphenyl 1 as a model substrate and potassium formate as the carbonyl source. After a comprehensive investigation of all the reaction parameters (see the ESI† for detailed information), we were delighted to find that upon irradiation of a solution of 4-iodobiphenyl 1 and potassium formate with blue light-emitting diodes (LEDs) in the presence of catalytic amounts of 4DPAIPN, Ni(PCy₃)₂Cl₂, and 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbbpy) in N,N-dimethylacetamide (DMA), 98% yield of the desired product 3 was obtained after methyl esterification with iodomethane, without observable formation of the by-product biphenyl (entry 1). The organic photocatalyst 4CzIPN could be used to catalyze the transformation with 92% yield (entries 2 and 3), and iridium-based photocatalysts Ir–I also promoted this transformation with moderate efficiency. Other nickel salts were also investigated (entries 4–7). The yield decreased sharply when other Ni(II) salts were used as the precatalysts, such as NiCl₂·glyme, NiBr₂·glyme, and Ni(acac)₂, but a 77% yield of 3 could be obtained when Ni(PPh₃)₂Cl₂ was used instead of Ni(PCy₃)₂Cl₂. From these results, we concluded that monodentate phosphine ligands play an important role in controlling the reactivity of the nickel catalysts. The monodentate phosphine ligand could possibly operate in synergy with the bidentate nitrogen ligand to stabilize the Ni(0) species A. Moreover, it should be noted that hydrodehalogenation of aryl halides by formate occurred smoothly under irradiation with blue LEDs, and we found that when DMA was replaced with dimethyl sulfoxide (DMSO) as a solvent, 52% yield of the hydrodeiodination product was detected. Other solvents, such as dioxane, THF, and acetone, failed to give the desired product 3. In addition, we explored other types of bidentate nitrogen ligands (see the ESI†) and found that 4,4′-dimethoxy-2,2′-bipyridine and 4,7-diphenyl-1,10-phenanthroline were also effective for this transformation. Finally, control experiments confirmed that the photocatalyst, nickel salt, and light were all indispensable for the desired reaction.

With the optimized conditions in hand, we then investigated the generality of this metallaphotoredox protocol with respect to aryl iodides. As depicted in Table 2, a variety of aryl iodides bearing electron-donating (–Me, –t-Bu, –OMe, and –SMe) or electron-withdrawing (–F, –Cl, –COOMe, and –CF₃) substituents reacted smoothly under the optimal conditions, furnishing the corresponding aryl carboxylic acids with good to excellent yields (60–98%). Moreover, aryl bromide (8), aryl aldehyde (13), aryl ketone (15), unprotected phenolic hydroxyl (16), unsubstituted amide (17), and even aryl pinacol boronate (11), which is susceptible to transmetallation under nickel catalysis, were well tolerated under the reaction conditions. This highlights the potential uses of this method in combination with further coupling transformations. 2-Iodonaphthalene also underwent the reaction smoothly and gave the desired product 20 in 89% yield. Notably, 1,4-diiodobenzene successfully underwent deiodocarboxylation smoothly in this system to deliver terephthalic acid (21) in 65% yield. The derivative of triclosan (22), a broad-spectrum antibacterial agent, was also an amenable substrate in this protocol.

Table 1 Optimization of carboxylation of aryl iodide^a

Entry	Variation from standard conditions	Yield of 3 (%)
a Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), HCOOK (0.3 mmol, 1.5 equiv.), 4DPAIPN (1.0 mol%), Ni(PCy3)2Cl2 (5.0 mol%), dtbbpy (6.0 mol%), and DMA (2.0 mL), and irradiation with blue LEDs (440 nm) at room temperature for 20 h under an argon atmosphere. The yield was determined by gas chromatography analysis. Isolated yield in parentheses.
1	None	98 (92)
2	4CzIPN instead of 4DPAIPN	92
3	Ir–I instead of 4DPAIPN	87
4	NiCl2·glyme	21
5	NiBr2·glyme	24
6	Ni(acac)2	15
7	Ni(PPh3)2Cl2	77
8	DMSO instead of DMA	36
9	Dioxane instead of DMA	Trace
10	THF instead of DMA	Trace
11	Acetone instead of DMA	Trace
12	No PC, or Ni-cat., or light	0

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Table 2 Scope of aryl iodides^a

a Reaction conditions as shown in Table 1, entry 1. Isolated yields.

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Based on the successful carboxylation of aryl iodides, we turned our attention to the suitability of aryl bromides for this transformation. Such reactions cannot be realized using the nickel-catalyzed strategy with formate through the thermal pathway developed in our earlier work.^17a To our delight, when a catalytic amount of tetrabutylammonium iodide (TBAI) was added to the reaction system, the desired product 3 was detected in 97% yield (see the ESI† for detailed information). The use of catalytic iodine anions was essential for the reaction, possibly for accelerating the reduction of Ni(I) to Ni(0) or mediating the in situ formation of organ-iodide electrophiles.¹⁹ In addition, to highlight the synthetic utility of this metallaphotoredox debromocarboxylation, a gram-scale reaction of 4-bromobiphenyl 23 was performed. The reaction proceeded smoothly and the amount of photocatalyst could be reduced to 0.5 mol%, affording 4-biphenylcarboxylic acid 24 in 92% isolated yield.

This protocol showed exquisite functional group tolerance (Table 3). A wide range of aryl bromides bearing different functional groups, such as ether (25, 29, 31–33), amine (26), trifluoromethyl (27), cyano (28), ketone (30), amino acid (34), phenolic hydroxyl (35), and sulfone (36), on the arene backbone could be converted into the corresponding aryl carboxylic acid in good to excellent yields (60–95%). Interestingly, the styrene fragment (37) and the electron-deficient C–C π-bond (38), which easily undergo hydrocarboxylation in the presence of formate through a photochemical process,^14,18 were compatible in this system, thus demonstrating that this method has excellent chemical selectivity. The ortho substituents of aryl bromide and aryl chloride failed to yield the desired product (see the ESI†). Interestingly, this carboxylation method was compatible with heteroaromatic rings, including quinolone (40), dibenzo[b,d]furan (41), dibenzo[b,d]thiophene (42), pyrimidine (43), and benzo[b]thiophene (44). Furthermore, the protocol was also extended to vinyl bromides. Both styryl bromide (45 and 46) and cyclohexenyl bromide (47 and 48) underwent the debromocarboxylation reaction smoothly. Notably, complex compounds that contained the bromo-substituted 1,3-butadiene fragment were also amenable substrates and gave the desired product 49 in good yields with the butadiene intact. These results highlight the potential synthetic value of this protocol for the synthesis of aryl and vinyl carboxylic acids.

Table 3 Scope of aryl bromides^a

a Reaction conditions: see the ESI.† Isolated yields.

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Isotopically labeled active pharmaceutical ingredients are of utmost importance in the field of lead compound drug discovery and the use of such compounds can provide vital information about drug metabolic and pharmacokinetic profiles.²⁰ Thus, we investigated the synthesis of ¹³C-labeled carboxyl acids to further demonstrate the practicality and versatility of our dehalocarboxylation protocol. As shown in Table 4, several ¹³C-labeled drug intermediates were obtained in moderate yields (50–55), which offers an operationally simple and practical tool to access isotopically labeled aryl carboxylic acids. In addition, the synthetic value of this strategy was demonstrated through application in several reported medicinally promising scaffolds, such as probenecid (56), carboxycelecoxib (57), ataluren (58), and tafamidis (59). Various functional groups, including amides, pyrazoles, unprotected sulfonamides, and oxadiazoles, were well tolerated. Notably, gram-scale synthesis of probenecid (56) was also efficiently realized with 0.5 mol% of the photocatalyst (5.0 mmol scale, 80% yield). Due to the excellent chemical selectivity of this method, we selected the simple 1-bromo-4-iodobenzene (60) as a starting substrate to synthesize tamibarotene (63), a retinoid drug for relapsed or refractory acute promyelocytic leukemia, through the processes of deiodocarboxylation, amidation, and debromocarboxylation. Gratifyingly, the double carbonyl ¹³C-isotope labeling of tamibarotene proceeded smoothly from a simple commercially available carbonyl source, ¹³C-labeled sodium formate. This reaction required the use of precious palladium catalysts and MePh₂Si¹³CO₂H as the carbonyl source in an earlier study.²¹

Table 4 Synthetic applications

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To shed light on the mechanism of the transformation, we conducted a series of preliminary mechanistic experiments. The ¹³C-labeling experiments were conducted under different gas (Ar, CO₂, and CO) atmospheres with ¹³C-labeled sodium formate as the carbonyl source (Scheme 3a). Deiodocarboxylation afforded ¹³C-labeled 24 in good-to-high yields with excellent ¹³C incorporation (>99% ¹³C incorporation). These results clearly demonstrated that the mechanism of our dehalocarboxylation protocol is distinct from the previously reported systems through visible-light-driven carboxylation of aryl halides with CO₂ ²² and also excluded the possibility of a carbonylation process with CO in the reaction process.^5,16a Consistent with the proposed mechanism shown in Scheme 2, Stern–Volmer luminescence-quenching experiments revealed that the formate salts quenched the excited-state photocatalyst, while 4-iodobiphenyl and a mixture of 4-iodobiphenyl, Ni(PPh₃)₂Cl₂, and dtbbpy did not show a significant quenching effect (Scheme 3b, please see the ESI† for more details). Furthermore, attempts were made to use 1,1-diphenylethylene to trap the CO₂ radical anion; the addition product 65 with 1,1-diphenylethylene was also detected. Finally, our stoichiometric study with Ni(II)–ArI 66 failed to give the corresponding product 14. This result indicates that a Ni(II)–aryl species is not involved in the catalytic cycle, making the alternative catalytic Ni^0/II/III pathway rather unlikely.²³ As a result, based on the above findings of the mechanistic studies and the previous reports,²⁴ a catalytic Ni^0/I/III pathway, proceeding via the capture of the CO₂ radical anion by Ni(0), followed by oxidative addition and then reductive elimination, is more operative in this catalytic process (Scheme 2).

Scheme 3 Mechanistic studies.

Conclusions

In summary, we have disclosed a novel and practical carboxylation of C(sp²)-halides with formate under photoredox nickel dual catalysis. This method has a broad scope of substrates, high selectivity, and remarkable functional group compatibility. The synthetic value of this protocol was highlighted by the synthesis of several commercial drugs, namely, probenecid, ataluren, tafamidis, and tamibarotene. Moreover, this approach also provides a complementary method that extends the range of the current methodologies available for accessing carbon-13 isotopically labeled carboxylic acids. We expect that engagement of the CO₂ radical anion in metal-mediated bond-forming strategies may unlock new platforms that can be used to introduce the carboxyl motif into specific molecular frameworks.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors acknowledge the support from the National Natural Science Foundation of China (grant numbers 21732006, 51821006, and 22101272). We thank X. Lu (USTC) for the helpful discussions.

References

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Footnotes

† Electronic supplementary information (ESI) available: Experimental protocols and spectral data. See DOI: https://doi.org/10.1039/d2qo01361d

‡ These authors contributed equally.

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