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Upgrading ketone synthesis direct from carboxylic acids and organohalides

Abstract

The ketone functional group has a unique reactivity in organic chemistry and is associated with a number of useful reactions. Catalytic methods for ketone synthesis are continually being developed. Here, we report a photoredox, nickel and phosphoranyl radical synergistic cross-electrophile coupling of commercially available chemicals, aromatic acids and aryl/alkyl bromides. This allows for concise synthesis of highly functionalized ketones directly, without the preparation of activated carbonyl intermediates or organometallic compounds, and thus complements the conventional Weinreb ketone synthesis. Use of the appropriate photocatalyst, ligand amount and solvents can match the reaction rate required by any simple catalytic cycle. The practicality and synthetic robustness of the reaction are illustrated by the facile synthesis of complex ketones from readily available feedstock chemicals.

Introduction

Ketones play a prominent role in organic chemistry. The ketone moiety is extremely common in natural products and pharmaceuticals1 and in dyes, fragrancies and flavors2. It is also a versatile reaction center in organic synthesis3. Many frequently used reactions, including the Mannich reaction, Wittig reaction, Grignard reaction, Passerini reaction, Baeyer–Villiger oxidation, and Wolff–Kishner–Huang reduction describe a wide array of transformations of ketones. The development of a practical route to ketones from feedstock chemicals has long been a subject of interest4,5,6,7,8,9,10,11,12. Carboxylic acids and organohalides are commercially abundant and structurally diverse, bench-stable feedstock chemicals commonly used in organic synthesis (Fig. 1a). When producing ketones from carboxylic acids and organohalides, the stoichiometric approach requires preparation of necessary intermediates such as amides or aldehydes and Grignard reagents13,14. If aldehydes are employed, reoxidation is necessary15. Catalytic strategies for production of ketones rely on transition metal-catalyzed carbon–carbon coupling between activated carbonyls such as acid chlorides or anhydrides with organometallic reagents (Fig. 1b)16,17,18,19. However, activated carbonyls are generally prepared in as many as three steps from carboxylic acids and organometallics are obtained typically by metalation of organohalides20, which can often lead to poor functional group compatibility or a lengthy functional group protection/deprotection process.

Fig. 1: Catalytic cross-electrophile coupling between carboxylic acids and organohalides.
figure1

a The abundant feedstock chemicals in synthetic lab. b Direct cross-electrophile coupling of acid and organohalides. c Key challenge: C–O versus C–C formation.

In recent years, nickel-catalyzed cross-electrophile coupling has attracted considerable attention21,22,23,24,25,26,27,28,29,30. The carbon–carbon coupling arises from two different electrophiles in the presence of stoichiometric reductant. We posited that a carboxylic acid could be directly used as a latent electrophile (C-terminus) rather than a nucleophile (O-terminus) in cross-coupling. This could simplify and upgrade ketone synthesis from carboxylic acids and organic halides13. Very recently, our group and Doyle et al. reported an elegant photoredox-promoted mild deoxygenation of carboxylic acids generating acyl radicals31,32,33,34,35. Since photoredox and nickel-catalyzed C–O bond formation between carboxylic acids and aromatic bromides has been reported36 to achieve the desired cross-electrophile coupling, acyl radical oxidative addition by a metallaphotoredox pathway37,38,39,40,41 is essential to suppress the C–O bond formation (Fig. 1c). Alternatively, a judicious strategy reported by Gong et al. is conversion of carboxylic acid into anhydrides in situ to suppress the C–O coupling22,23. However, the use of free carboxylic acids as acyl radical precursors is a challenge in the oxidative addition step as a result of the strong bond dissociation energy of the C–O bond (106 kcal mol−1)33.

A proposed mechanism for the designed metallaphotoredox cross-electrophile coupling is shown in Fig. 2. The photoexcited *[Ir(dF(CF3)ppy)2(dtbbpy)]PF6 [1/2Ered (*IrIII/IrII) = +1.21 V vs SCE, τ = 2.3 μs]38 causes single-electron transfer (SET) oxidation of triphenylphosphine (Ered = +0.98V vs SCE)31, as indicated by our Stern–Volmer experimental results (see Supplementary Fig. 7). The triphenylphosphine radical cation (I) generated recombines with the carboxylate anion to form a phosphoranyl radical intermediate (II). Owing to the strong affinity between the phosphoranyl radical and oxygen, a facile β-scission of the radical species (II) occurs, giving rise to a nucleophilic acyl radical42, which can undergo oxidative addition to the resulting aryl-NiII species (III) giving the NiIII species (IV)43,44,45. Finally, reductive elimination from the NiIII intermediate (IV) can generate the desired cross-electrophile coupling product, R-CO-Ar. A second SET event from IrII ([IrIII/IrII] = −1.37 V vs SCE), leading to an NiI species completes both catalytic cycles. The synergistic combination of photoredox with nickel catalysis proposed in Fig. 2 is a subject of continuing research46,47,48,49,50,51,52,53,54,55,56,57,58, and several challenges remain in this cross-electrophile coupling and must be addressed: (1) Efficient control of the matching of the C–O bond cleavage and the radical addition to the nickel center; (2) weakening of the interference of stoichiometric triphenylphosphine in the nickel catalytic unit; and (3) use of appropriate ligands and solvents to significantly suppress the C–O bond formation. Herein, we report a formal cross-electrophile coupling of carboxylic acids with aryl or alkyl halides enabled by photoredox and nickel catalysis, and phosphoranyl radical synergistic chemistry, leading to concise synthesis of ketones (Fig. 1b).

Fig. 2: Proposed mechanism.
figure2

Mechanistic proposal for cross-electrophile coupling of acid and aryl bromides. o.a. oxidative addition, r.e. reductive elimination.

Results

Reaction optimization

Our investigation of this cross-electrophile coupling began with the reaction of 4-methyl-benzoic acid (1) with 5-bromo-2-(trifluoromethyl) pyridine (2), and the representative results are presented in Table 1. The optimized reaction conditions include 2 mol% [Ir{dF(CF3)ppy}2{dtbbpy}]PF6, 3 mol% NiBr2.dme together with 5 mol% 4,4′-di-tert-butyl-2,2′-bipyridine (L1, Fig. 3) and 1.5 equiv Ph3P with a mixed DMF-CH3CN solvent (entry 1, Table 1). Under the standard conditions, the desired cross-electrophile coupling product (3) can be obtained in 82% yield while the yield of the C–O coupling process, giving 3′ is suppressed to 16%. We found the loading amount of ligand plays an important role in the control of the C–C and C–O bond formation (entries 2–4, Table 1). An increased or decreased loading amount of 4,4′-di-tert-butyl-2,2’-bipyridine can facilitate the formation of the C–O coupling by-product (3′). Screening of different ligands and solvents indicated that both a ligand effect and a solvent effect are crucial for a successful cross-electrophile coupling (entries 5–11, Table 1). We speculated that only compatible consecutive steps with well-matched rates would benefit this cross-electrophile coupling. In the absence of either photocatalyst, NiBr2·dme, triphenylphosphine or light irradiation, the model reaction failed to occur. The quantum yield of the model reaction was determined to be 0.35, arguing against a radical chain pathway.

Table 1 Optimization of the reaction conditions.
Fig. 3: Photocatalysts and ligands.
figure3

Catalysts and ligands for cross-electrophile coupling of acid and aryl bromides.

Substrate scope

With the optimized conditions in hand, we investigated the scope of the cross-electrophile coupling reaction with regard to aromatic carboxylic acids, and obtained the results in Fig. 4. In general, this protocol is highly efficient and has a broad substrate scope. The electron-rich and electron-poor functional groups on the ortho-, meta-, and para-positions on the phenyl groups of the aromatic acids have little influence on the coupling process and the desired ketones (3–21) are formed in 62–83% yield. A series of useful functional groups, such as bromine (6), reactive carbonyl groups (13–16), a terminal alkene (18), an internal alkyne (19) and an acetal (21) tolerate the reaction conditions well. Some of these functional groups have difficulty surviving the conventional Weinreb ketone synthesis method toward Grignard reagents. Hetero-aromatic carboxylic acids are satisfactory starting materials and can uniformly produce the synthetically valuable diheteroaromatic ketones (22–26) with moderate to good yields. However, examination of the reaction of aliphatic carboxylic acids under these standard conditions showed that only a trace amount of the desired product can be produced while both decarboxylative C–C coupling and direct C–O coupling can occur.

Fig. 4: Carboxylic acid scope at a 0.2 mmol scale under standard conditions.
figure4

The isolated yield of ketone is given for product and the GC ratio of ketone and ester is given in parenthesis. aThe ratio of ketone and ester is calculated based on isolation.

Subsequently, we studied the substrate scope of aromatic bromides (Fig. 5) and found that many commercially available aromatic bromides can be used to deliver the desired ketones (27–46) in good yields. The excellent functional group tolerance of –COOR (28, 33, 44, 45), –CN (29, 34), terminal unsaturated chemical bonds (43, 44), and heteroarenes (38–43, 46) support the practicality of the reaction. With this strategy, it is also very easy to construct fluorine- and fluoroalkyl-containing diaryl ketones (30–32, 36, 37, 39–42) with acceptable yields. Several alkyl halides also serve as coupling partners in this cross-electrophile coupling reaction, leading to functionalized ketones (47–49) in good yields (up to 92%). When benzyl chloride was employed, 46% yield of ketone (49) was obtained and a significant amount of by-product ester was formed possibly because of the nucleophilic substitution side reaction. This coupling reaction can allow for the construction of highly functionalized ketones in an operationally simple, step-economical and gram-scale reaction (29, 5 mmol scale).

Fig. 5: Organohalide scope on a 0.2 mmol scale under standard conditions.
figure5

The isolated yield of ketone is given and the GC ratio of ketone and ester is given in parenthesis. aThe ratio of ketone and ester is calculated based on isolation. bBenzyl chloride was used.

Synthetic application

To further demonstrate the synthetic robustness of the reaction, we applied the strategy for the construction of a series of complex ketones from carboxylic acids and aromatic bromides (Fig. 6). Fenofibrate (50) is a drug used to adjust lipid levels and blood viscosity and it could be prepared in one step in 65% yield. The complex ketones (50–55) can be obtained in synthetically useful yields. The precise cross-electrophile coupling also allows for introduction of functional groups at an early synthetic stage to limit the number of synthetic steps thus improving the efficiency.

Fig. 6: Concise synthesis of complex ketones.
figure6

Carboxylic acids are blue and aromatic bromides are pink. The isolated yield of by-product ester is given in parenthesis.

Mechanism of stoichiometric reactions

We performed the stoichiometric reactions of Ar–Ni(II) intermediate (56) with 1.5 equiv. Ph3P in DMF/MeCN. Interestingly, no ligand exchange was observed by 31P NMR analysis (Fig. 7, also see Supplementary Fig. 10). Treatment of Ar–Ni(II) intermediate (56) under the photoredox conditions, led to the desired deoxygenative C–C coupling product (35), which was obtained in 42% yield, further supporting the proposed mechanism (Fig. 7).

Fig. 7: Mechanistic studies.
figure7

a The reaction of Ph3P with Ar–Ni(II) intermediates. b Stoichiometric reactions of Ar–Ni(II) intermediates.

Discussion

We have developed a cross-electrophile coupling between aromatic carboxylic acids and organic bromides, inexpensive and abundant feedstock chemicals, enabled by photoredox and a nickel and phosphoranyl radical synergistic combination, affording a wide array of structurally diverse ketones with excellent functional group compatibility. This strategy for ketone synthesis can significantly improve the synthetic efficiency and step-economy, and it also opens a door to construct highly functionalized or complex ketones which are still difficult to prepare by a conventional Weinreb ketone synthesis. We found that the use of appropriate ligand loading amount (5 mol% of 4,4′-di-tert-butyl-2,2′-bipyridine), mixed solvents (DMF/CH3CN) and combined inorganic bases (K3PO4 and Cs2CO3) is crucial to achieve the desired C–C bond formation reactions, affording the desired ketone products. The employment of more or less of ligand results in a sharply decreased yield of the ketone product and an increased yield of the ester by-product. Use of combined bases and mixed solvents would improve the deprotonation of carboxylic acids to expedite the acyl radical generation and use of the precise amount of a ligand would promote the acyl radical oxidative addition to the arylnickel (II) species. We speculated that a facile C–O bond cleavage and subsequent rapid acyl radical oxidative addition rate can control the selective C–C bond formation. We believe this cross-electrophile coupling strategy of carboxylic acids and organic halides will upgrade the synthesis of ketones with great potential application in organic synthesis, drug discovery and optochemical biology given the importance and ubiquity of ketones.

Methods

General procedure for cross-electrophile coupling of carboxylic acids and organohalides

Preparation of Ni-based catalyst solution: In the nitrogen-filled glove box, a stirring bar, NiBr2·dme (1.9 mg, 3.0 mol%), 4,4′-di-tert-butyl-2,2′-bipyridine (2.7 mg, 5.0 mol%) and CH3CN/DMF (2.0 mL, V/V = 1:1) were successively added to an oven-dried vial (8 mL screw-cap threaded). The vial was then sealed with a Teflon-lined plastic screw-cap and stirred until the resulting mixture become homogeneous (about 20 min).

Photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.5 mg, 2 mol%), aromatic carboxylic acid (0.2 mmol, 1.0 equiv), aryl bromide (0.4 mmol, 2.0 equiv), Ph3P (78.6 mg, 0.3 mmol, 1.5 equiv), anhydrous powder K3PO4 (42.4 mg, 0.2 mmol, 1.0 equiv), and anhydrous powder Cs2CO3 (65.0 mg, 0.2 mmol, 1.0 equiv) were added to an oven-dried 10 mL Schlenk tube equipped with a magnetic stirring bar. The tube was evacuated and backfilled with argon three times. Subsequently, the nickel-catalyst solution was transferred into this Schlenk tube under argon. The tube was then sealed and placed ~5 cm from 2 × 45 W blue LEDs. The reaction mixture was stirred for 20–36 h at room temperature (air-condition was used to keep the temperature is 25 °C or so). After completion, the reaction mixture was removed from the light, diluted with water and the aqueous layer was extracted with EtOAc (3 × 2.0 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to afford the corresponding ketone products.

Data availability

The authors declare that all other data supporting the findings of this study are available within the article and Supplementary Information files, and also are available from the corresponding author upon reasonable request.

References

  1. 1.

    McDaniel, R. et al. Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel “unnatural” natural products. Proc. Natl Acad. Sci. USA 96, 1846–1851 (1999).

    ADS  CAS  PubMed  Google Scholar 

  2. 2.

    Tan, Y. & Siebert, K. J. Quantitative structure-activity relationship modeling of alcohol, ester, aldehyde, and ketone flavor thresholds in beer from molecular features. J. Agric. Food Chem. 52, 3057–3064 (2004).

    CAS  PubMed  Google Scholar 

  3. 3.

    Otera, J. (ed.) Modern Carbonyl Chemistry (Wiley-VCH, 2000).

  4. 4.

    Brunet, J. J. & Chauvin, R. Synthesis of diarylketones through carbonylative coupling. Chem. Soc. Rev. 24, 89–95 (1995).

    CAS  Google Scholar 

  5. 5.

    Li, Y., Hu, Y. & Wu, X. F. Non-noble metal-catalysed carbonylative transformations. Chem. Soc. Rev. 47, 172–194 (2018).

    ADS  PubMed  Google Scholar 

  6. 6.

    Ruan, J., Saidi, O., Iggo, J. A. & Xiao, J. Direct acylation of aryl bromides with aldehydes by palladium catalysis. J. Am. Chem. Soc. 130, 10510–10511 (2008).

    CAS  PubMed  Google Scholar 

  7. 7.

    Jiang, X., Zhang, M.-M., Xiong, W., Lu, L.-Q. & Xiao, W.-J. Deaminative (carbonylative) alkyl-Heck-type reactions enabled by photocatalytic C-N bond activation. Angew. Chem. Int. Ed. 58, 2402–2406 (2019).

    CAS  Google Scholar 

  8. 8.

    Wang, J., Cary, B. P., Beyer, P. D., Gellman, S. H. & Weix, D. J. Ketones from nickel-catalyzed decarboxylative, non-symmetric cross-electrophile coupling of carboxylic acid esters. Angew. Chem. Int. Ed. 58, 12081–12085 (2019).

    CAS  Google Scholar 

  9. 9.

    Bergonzini, G., Cassani, C. & Wallentin, C.-J. Acyl radicals from aromatic carboxylic acids by means of visible-light photoredox catalysis. Angew. Chem. Int. Ed. 54, 14066–14069 (2015).

    CAS  Google Scholar 

  10. 10.

    Dong, Z., Wang, J., Ren, Z. & Dong, G. Ortho C-H acylation of aryl iodides by palladium/norbornene catalysis. Angew. Chem. Int. Ed. 54, 12664–12668 (2015).

    CAS  Google Scholar 

  11. 11.

    Fu, M. C., Shang, R., Zhao, B., Wang, B. & Fu, Y. Photocatalytic decarboxylative alkylations mediated by triphenylphosphine and sodium iodide. Science 363, 1429–1434 (2019).

    ADS  CAS  PubMed  Google Scholar 

  12. 12.

    Shi, R. & Hu, X. From alkyl halides to ketones: nickel-catalyzed reductive carbonylation utilizing ethyl chloroformate as the carbonyl source. Angew. Chem. Int. Ed. 58, 7454–7458 (2019).

    CAS  Google Scholar 

  13. 13.

    Nahm, S. & Weinreb, S. M. N-methoxy-N-methylamides as effective acylating agents. Tetrahedron Lett. 22, 3815–3818 (1981).

    CAS  Google Scholar 

  14. 14.

    Bechara, W. S., Pelletier, G. & Charette, A. B. Chemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondary amides. Nat. Chem. 4, 228–234 (2012).

    CAS  PubMed  Google Scholar 

  15. 15.

    Steves, J. E. & Stahl, S. S. Copper(I)/ABNO-catalyzed aerobic alcohol oxidation: alleviating steric and electronic constraints of Cu/TEMPO catalyst systems. J. Am. Chem. Soc. 135, 15742–15745 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Wu, X. F., Neumann, H. & Beller, M. Palladium-catalyzed carbonylative coupling reactions between Ar-X and carbon nucleophiles. Chem. Soc. Rev. 40, 4986–5009 (2011).

    CAS  PubMed  Google Scholar 

  17. 17.

    Guo, L. & Rueping, M. Decarbonylative cross-couplings: nickel catalyzed functional group interconversion strategies for the construction of complex organic molecules. Acc. Chem. Res. 51, 1185–1195 (2018).

    CAS  PubMed  Google Scholar 

  18. 18.

    Wang, D. & Zhang, Z. Palladium-catalyzed cross-coupling reactions of carboxylic anhydrides with organozinc reagents. Org. Lett. 5, 4645–4648 (2003).

    CAS  PubMed  Google Scholar 

  19. 19.

    Ben Halima, T. et al. Palladium-catalyzed Suzuki-Miyaura coupling of aryl esters. J. Am. Chem. Soc. 139, 1311–1318 (2017).

    PubMed  Google Scholar 

  20. 20.

    Hartwig, J. F. In Organotransition Metal Chemistry: from Bonding to Catalysis (University Science Books, Sausalito, 2010).

  21. 21.

    Biswas, S. & Weix, D. J. Mechanism and selectivity in nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides. J. Am. Chem. Soc. 135, 16192–16197 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Zhao, C., Jia, X., Wang, X. & Gong, H. Ni-catalyzed reductive coupling of alkyl acids with unactivated tertiary alkyl and glycosyl halides. J. Am. Chem. Soc. 136, 17645–17651 (2014).

    CAS  PubMed  Google Scholar 

  23. 23.

    Yin, H., Zhao, C., You, H., Lin, K. & Gong, H. Mild ketone formation via Ni-catalyzed reductive coupling of unactivated alkyl halides with acid anhydrides. Chem. Commun 48, 7034–7036 (2012).

    CAS  Google Scholar 

  24. 24.

    Ackerman, L. K., Lovell, M. M. & Weix, D. J. Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates. Nature 524, 454–457 (2015).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Wang, X., Wang, S., Xue, W. & Gong, H. Nickel-catalyzed reductive coupling of aryl bromides with tertiary alkyl halides. J. Am. Chem. Soc. 137, 11562–11565 (2015).

    CAS  PubMed  Google Scholar 

  26. 26.

    Jin, Y. & Wang, C. Nickel‐catalyzed asymmetric reductive arylalkylation of unactivated alkenes. Angew. Chem. Int. Ed. 131, 6794–6798 (2019).

    Google Scholar 

  27. 27.

    Ye, Y., Chen, H., Sessler, J. L. & Gong, H. Zn-mediated fragmentation of tertiary alkyl oxalates enabling formation of alkylated and arylated quaternary carbon centers. J. Am. Chem. Soc. 141, 820–824 (2019).

    CAS  PubMed  Google Scholar 

  28. 28.

    Ni, S. et al. Ni-catalyzed deaminative cross-electrophile coupling of Katritzky salts with halides via C horizontal line N bond activation. Sci. Adv. 5, eaaw9516 (2019).

    ADS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Poremba, K. E., Kadunce, N. T., Suzuki, N., Cherney, A. H. & Reisman, S. E. Nickel-catalyzed asymmetric reductive cross-coupling to access 1,1-diarylalkanes. J. Am. Chem. Soc. 139, 5684–5687 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    He, R.-D. et al. Reductive coupling between C–N and C–O electrophiles. J. Am. Chem. Soc. 141, 12481–12486 (2019).

    CAS  PubMed  Google Scholar 

  31. 31.

    Zhang, M., Xie, J. & Zhu, C. A general deoxygenation approach for synthesis of ketones from aromatic carboxylic acids and alkenes. Nat. Commun. 9, 3517 (2018).

    ADS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Zhang, M., Yuan, X.-A., Zhu, C. & Xie, J. Deoxygenative deuteration of carboxylic acids with D2O. Angew. Chem. Int. Ed. 58, 312–316 (2019).

    CAS  Google Scholar 

  33. 33.

    Ruzi, R. et al. Deoxygenative arylation of carboxylic acids by aryl migration. Chem. Eur. J. 25, 12724–12729 (2019).

    CAS  PubMed  Google Scholar 

  34. 34.

    Stache, E. E., Ertel, A. B., Tomislav, R. & Doyle, A. G. Generation of phosphoranyl radicals via photoredox catalysis enables voltage-independent activation of strong C-O bonds. Acs. Catal. 8, 11134–11139 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Mao, R., Bera, S., Cheseaux, A. & Hu, X. Deoxygenative trifluoromethylthiolation of carboxylic acids. Chem. Sci. 10, 9555–9559 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Welin, E. R., Le, C., Arias-Rotondo, D. M., McCusker, J. K. & MacMillan, D. W. Photosensitized, energy transfer-mediated organometallic catalysis through electronically excited nickel(II). Science 355, 380–385 (2017).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Twilton, J. et al. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052 (2017).

    CAS  Google Scholar 

  38. 38.

    Prier, C. K., Rankic, D. A. & MacMillan, D. W. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Milligan, J. A., Phelan, J. P., Badir, S. O. & Molander, G. A. Alkyl carbon-carbon bond formation by nickel/photoredox cross-coupling. Angew. Chem. Int. Ed. 58, 6152–6163 (2019).

    CAS  Google Scholar 

  40. 40.

    Skubi, K. L., Blum, T. R. & Yoon, T. P. Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Wang, C. S., Dixneuf, P. H. & Soule, J. F. Photoredox catalysis for building C-C bonds from C(sp2)-H bonds. Chem. Rev. 118, 7532–7585 (2018).

    CAS  PubMed  Google Scholar 

  42. 42.

    Schiavon, G., Zecchin, S., Cogoni, G. & Bontempelli, G. Anodic oxidation of triphenylphosphine at a platinum electrode in acetonitrile medium. J. Electroanal. Chem. Interfac. 48, 425–431 (1973).

    CAS  Google Scholar 

  43. 43.

    Zhang, X. & MacMillan, D. W. C. Direct aldehyde C-H arylation and alkylation via the combination of nickel, hydrogen atom transfer, and photoredox catalysis. J. Am. Chem. Soc. 139, 11353–11356 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Schirmer, T. E., Wimmer, A., Weinzierl, F. W. C. & König, B. Photo–nickel dual catalytic benzoylation of aryl bromides. Chem. Commun. 55, 10796–10799 (2019).

    CAS  Google Scholar 

  45. 45.

    Chu, L., Lipshultz, J. M. & MacMillan, D. W. Merging Photoredox and nickel catalysis: the direct synthesis of ketones by the decarboxylative arylation of alpha-oxo acids. Angew. Chem. Int. Ed. 54, 7929–7933 (2015).

    CAS  Google Scholar 

  46. 46.

    Smith, R. T. et al. Metallaphotoredox-catalyzed cross-electrophile Csp(3)-Csp(3) coupling of aliphatic bromides. J. Am. Chem. Soc. 140, 17433–17438 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Konev, M. O., McTeague, T. A. & Johannes, J. W. Nickel-catalyzed photoredox-mediated cross-coupling of aryl electrophiles and aryl azides. ACS Catal. 8, 9120–9124 (2018).

    CAS  Google Scholar 

  48. 48.

    Ackerman, L. K. G., Martinez Alvarado, J. I. & Doyle, A. G. Direct C-C bond formation from alkanes using Ni-photoredox catalysis. J. Am. Chem. Soc. 140, 14059–14063 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Zhu, C. et al. A multicomponent synthesis of stereodefined olefins via nickel catalysis and single electron/triplet energy transfer. Nat. Catal. 2, 678–687 (2019).

    CAS  Google Scholar 

  50. 50.

    Yan, D.-M., Xiao, C. & Chen, J.-R. Strong C(sp3)-H arylation by synergistic decatungstate photo-HAT and nickel. Catal. Chem. 4, 2496–2498 (2018).

    CAS  Google Scholar 

  51. 51.

    Meng, Q.-Y., Wang, S., Huff, G. S. & König, B. Ligand-controlled regioselective hydrocarboxylation of styrenes with CO2 by combining visible light and nickel catalysis. J. Am. Chem. Soc. 140, 3198–3201 (2018).

    CAS  PubMed  Google Scholar 

  52. 52.

    Johnston, C. P., Smith, R. T., Allmendinger, S. & MacMillan, D. W. Metallaphotoredox-catalysed sp(3)-sp(3) cross-coupling of carboxylic acids with alkyl halides. Nature 536, 322–325 (2016).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Li, J., Luo, Y., Cheo, H. W., Lan, Y. & Wu, J. Photoredox-catalysis-modulated, nickel-catalyzed divergent difunctionalization of ethylene. Chemistry 5, 192–203 (2019).

    CAS  Google Scholar 

  54. 54.

    Le, C. C. & MacMillan, D. W. Fragment couplings via CO2 extrusion-recombination: expansion of a classic bond-forming strategy via metallaphotoredox. J. Am. Chem. Soc. 137, 11938–11941 (2015).

    CAS  PubMed  Google Scholar 

  55. 55.

    Joe, C. L. & Doyle, A. G. Direct acylation of Csp(3)-H bonds enabled by nickel and photoredox catalysis. Angew. Chem. Int. Ed. 55, 4040–4043 (2016).

    CAS  Google Scholar 

  56. 56.

    Leeuwen, T., Buzzetti, L., Perego, L. A. & Melchiorre, P. A redox-active nickel complex that acts as an electron mediator in photochemical Giese reactions. Angew. Chem. Int. Ed. 58, 4953–4957 (2019).

    Google Scholar 

  57. 57.

    Zhang, L. & Hashmi, A. S. K. The combination of benzaldehyde and nickel-catalyzed photoredox alkylation/arylation. Angew. Chem. Int. Ed. 58, 1823–1827 (2019).

    Google Scholar 

  58. 58.

    Si, X., Zhang, L. & Hashmi, A. S. K. Benzaldehyde- and nickel-catalyzed photoredox C(sp3)-H alkylation/arylation with amides and thioethers. Org. Lett. 21, 6329–6332 (2019).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the National Natural Science Foundation of China (21971108, 21971111, 21702098, 21732003, and 21672099), the Natural Science Foundation of Jiangsu Province (Grant No. BK20190006), Fundamental Research Funds for the Central Universities (020514380214), “Innovation & Entrepreneurship Talents Plan” of Jiangsu Province, “1000‐Youth Talents Plan”, “Jiangsu Six Peak Talent Project”, and start-up funds from Nanjing University for financial support. Y.L., K.L., C.Z., and W.X. are warmly acknowledged to reproduce experimental procedures for products (3, 23, 24 and 34).

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J.X. conceived and supervised the whole project and wrote the paper with input from all authors. R.R., C.Z., and J.X. designed and discussed the experiments; R.R. and K.L. performed and analyzed the experiments.

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Correspondence to Jin Xie.

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J.X., R.R., and K.L. declare the following competing interests that one Chinese patent has been registered (201910828905.0). All other authors declare no competing interest.

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Ruzi, R., Liu, K., Zhu, C. et al. Upgrading ketone synthesis direct from carboxylic acids and organohalides. Nat Commun 11, 3312 (2020). https://doi.org/10.1038/s41467-020-17224-2

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