Non-symmetrical diarylcarboxylic acids via rhodium(I)-catalyzed regiospecific cross-dehydrogenation coupling of aromatic acids: twofold direct C–H bond activations in water

Abstract

A rhodium-catalyzed direct cross-dehydrogenative coupling reaction between two different aromatic acids to generate non-symmetrical diaryl acids was developed for the first time. This reaction is operationally simple, tolerant to air, compatible with water, and it can be easily scaled up to gram level by using 0.2 mol% of the catalyst.

---

Introduction

2,2′-Diaryl acids are important motifs, which are widely present in various high-performance polymers,¹ metal–organic frameworks (MOFs),² natural products,³ pharmaceutical agents,⁴ and C2-symmetric ligands.⁵ Compared with symmetrical diaryl acids, the non-symmetrical diaryl acids are even more structurally appealing and have broader applications. Despite their importance, the synthetic strategies for obtaining unsymmetrical diaryl acids are very limited. The popular approach toward such structures is via the Ullmann-type coupling reaction, either intramolecularly or intermolecularly (Scheme 1a).⁶ However, the requirement of halogen prefunctionalization of the aromatic ring as well as its non-compatibility with free acids resulted in increased reaction steps and limited scope to only a small number of diaryl acids. Another common method for non-symmetrical diaryl acids is the oxidative cleavage of phenanthrene⁷ and phenanthrene-9,10-dione (Scheme 1b),⁸ or the oxidation of alkyl-substituted 2-biphenylcarboxylic acid (Scheme 1b).⁹ However, the requirement of pre-existing biaryl structure in the substrate limits its practicability and generality. Thus, a method for obtaining non-symmetrical diaryl acids moieties directly from simple aryl carboxylic acids is highly desirable.

Scheme 1 Strategies for synthesizing non-symmetrical diaryl acids.

Cross-dehydrogenative coupling (CDC) reaction can directly couple two different C–H bonds to generate new C–C bonds, and does not require any substrate prefunctionalization. Such reactions cannot only minimize the reaction steps, but also reduce overall waste and increase natural resource utilization, thus contributing to greener and more sustainable chemistry. Despite these apparent advantages, CDC reaction of simple aromatic acids remains a challenge because of the unfavorable thermodynamics, low reactivity of aromatic-H bonds, and selectivity issues with aryl acids.^10,11 To the best of our knowledge, no general method for synthesizing non-symmetrical diaryl acids via the CDC reaction of two simple aromatic acids currently exists. As part of our continuous research in dehydrogenative coupling reactions of aromatic carboxylic acids,¹² in the present paper, we describe an efficient and regiospecific CDC reaction of two simple aromatic acids to achieve a wide range of non-symmetrical diaryl acids for the first time (Scheme 1c).

Results and discussion

Previously, we have reported a homo-dehydrogenative coupling reaction of aromatic carboxylic acids to synthesize symmetrical diaryl acids.¹² Due to the similarity of various aromatic acids, it is much more challenging to find a method for selective coupling of two different aromatic acids via twofold C–H activations.

Nevertheless, we reasoned that it is possible to achieve such selectivity because the rhodium catalyst can sequentially activate two different aryl C–H bonds due to the changes of electronic properties before and after the first C–H bond activation (Scheme 2). To test this hypothesis, the CDC reaction of 2-methoxybenzoic acid (0.1 mmol) and 2-chlorobenzoic acid (0.3 mmol) was investigated as a model reaction. We are pleasantly surprised to find that a good yield (70%) of CDC non-symmetrical diaryl acid was achieved with 5 mol% [Rh(nbd)Cl]₂ and 5 equiv. MnO₂ at 150 °C under air in 1 mL water for 24 h (please see ESI†). In the aforementioned model reaction, the homo-coupling product is obtained at a yield of 27% (3,3′-dimethoxybiphenyl-2,2′-dicarboxylic acid, based on 2-methoxybenzoic acid) and 50% (3,3′-dichlorobiphenyl-2,2′-dicarboxylic acid, based on 2-chlorobenzoic acid) respectively.

Scheme 2 The control of CDC reaction between two different aromatic acids.

Results show that to successfully achieve non-symmetrical coupling, one of the substrate with electron-donating substituents at the benzene ring is important. In all these cases, the coupling partner with electron-donating substituents or with halogen substituents underwent the CDC reaction in moderate to good yields (Table 1, 3a–w). Phenyl-substituted benzoic acid also proceeded well, resulted in a moderate yield (Table 1, 3x). The CDC reaction between electron-donating group-substituted benzoic acid and strong electron-withdrawing group-substituted benzoic acid can also achieve a moderate yield (Table 1, 3y–zc). In most cases, if both substrates are benzoic acid with electron-withdrawing substituents, the cross-coupling product would be obtained at a very low yield. While the CDC reaction of ortho-chlorobenzoic acid and ortho-nitrobenzene acid give 45% yield (Table 1, 3zd). Importantly, the CDC reaction was also successful for gram-scale transformation, giving a comparable yield by using a much lower amount of catalyst (0.2 mol%) with a longer reaction time (96 h) (Table 1, 3e). This result also indicated that the loading of catalysts might be reduced by using a longer reaction time.

Table 1 Synthesis of non-symmetrical diaryl acids via CDC reactions of aromatic carboxylic acids^a

a All reactions were carried out with aromatic acid A (0.1 mmol, left ring), aromatic acid B (0.3 mmol, right ring) [Rh(nbd)Cl]₂ (10 mol%), and MnO₂ (5 equiv.) in a sealed tube in 1 mL H₂O at 150 °C for 24 h unless otherwise stated. The acid was obtained after purification by TLC, which was then dissolved in 1 mL acetone, and CH₃I (>0.5 mmol), K₂CO₃ (1 mmol) were added to react at 60 °C for 24 h to give the diester. All yields are referred to the isolated dimethylesters.b Aromatic acid A (1 g, 6.6 mmol) and aromatic acid B (2.7 g, 19.4 mmol), catalyst (6.9 mg, 0.2 mol%), MnO₂ (2.9 g, 33.3 mmol) in 5 mL H₂O for 96 h, the yield was the isolated yield of aromatic acid.

---

Based on our previous study on rhodium-catalyzed carboxyl-directed homo-dehydrogenative coupling reactions of aromatic carboxylic acids¹² and other reference,¹³ a reasonable mechanism for this process is proposed in Scheme 3. The initial rhodium(I)-catalyst may be oxidized to the active rhodium(III) catalyst by the oxidant MnO₂. Afterward, a rhodium(III)-initiated dual cyclometallation and a subsequent reductive elimination would produce the CDC product, and regenerate the rhodium(I) species.

Scheme 3 Proposed mechanism for the rhodium-catalyzed CDC reaction of aromatic acids.

Conclusions

In summary, a direct CDC reaction between two different benzoic acid derivatives to generate non-symmetrical diaryl acids was developed for the first time by using MnO₂ as oxidant under air in water. This strategy has several advantages: (1) simple benzoic acid derivatives were used directly; (2) the procedure is operationally simple, tolerant to air, and compatible with water; (3) this reaction can be easily scaled up to the gram-scale level with low rhodium catalyst loading (0.2 mol%).

Experimental section

In a typical experimental procedure, a solution of an aromatic acid A (0.1 mmol), aromatic acid B (0.3 mmol), [Rh(nbd)Cl]₂ (4.6 mg, 0.01 mmol), and activated MnO₂ (purchased from Aldrich and used as received, 45 mg, 0.5 mmol) in distilled water (1.0 mL) was stirred in a sealed tube under an atmosphere of air at 150 °C for 24 h. The reaction mixture was then cooled to room temperature and acidified by dilute HCl to pH < 3, and then the solvent was evaporated in vacuo. The residue was dissolved in THF and filtered through a 1-inch plug of silica gel to remove the salts. Afterward, the solvent was evaporated in vacuo. The residue was dissolved in 1 mL acetone, and 0.5 mmol CH₃I and 1.0 mmol K₂CO₃ were added to react at 60 °C for 24 h. The pure product was obtained by preparative thin-layer chromatography on silica gel with petroleum ether and ethyl acetate as eluent.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (No. 21402168) and Scientific Research Foundation of Hunan Provincial Education Department (No. 15B232) as well as the NSERC, FQRNT, CFI, and the Canada Research Chair (to C.-J. Li) for their support of our research.

Notes and references

1. (a) Polyimides Fundamentals and Applications, ed. M. K. Ghosh and K. L. Mittal, Marcel Dekker, New York, 1996; (b) Photosensitive Polyimides Fundamentals and Applications, ed. K. Horie and T. Yamashita, Technomic, Lancaster, 1995; (c) K. Sakayori, Y. Shibasaki and M. Ueda, J. Polym. Sci., Part A: Polym. Chem., 2006, 44, 6385.
2. (a) T. Zhang and W. Lin, Chem. Soc. Rev., 2014, 43, 5982; (b) D. S. Li, Y.-P. Wu, J. Zhao, J. Zhang and J. Y. Lu, Coord. Chem. Rev., 2014, 261, 1; (c) H.-X. Zhang, F. Wang, H. Yang, Y.-X. Tan, J. Zhang and X. Bu, J. Am. Chem. Soc., 2011, 133, 11884; (d) Y. H. Zhang, X. Li and S. Song, Chem. Commun., 2013, 49, 10397; (e) S. Bhattacharya, A. Goswami, B. Gole, S. Ganguly, S. Bala, S. Sengupta, S. Khanra and R. Mondal, Cryst. Growth Des., 2014, 14, 2853; (f) S. Guo, D. Tian, Y. Luo and H. Zhang, J. Coord. Chem., 2012, 65, 308.
3. (a) L. Jurd, J. Am. Chem. Soc., 1958, 80, 2249; (b) D.-F. Chen, S.-X. Zhang, L. Xie, J.-X. Xie, K. Chen, Y. Kashiwada, B. N. Zhou, P. Wang, L. M. Cosentino and K.-H. Lee, Bioorg. Med. Chem., 1997, 5, 1715; (c) A. R. M. S. Brito, F. M. D. Faria, M. A. D. Silva, L. C. D. Santos, W. Vilegas, PCT Int. Appl. WO 2014071480A1, 2014; (d) T. D. Nelson and A. I. Meyers, J. Org. Chem., 1994, 59, 2577.
4. (a) Y. Liu, D. Zhang, D. Zou, Y. Wang, C. Duan, L. Jia, P. Xie, F. Feng, F. Wang, X. X. Zhang and Q. Zhang, J. Biomed. Nanotechnol., 2011, 7, 621; (b) J. Jin, H. Sun, H. Wei and G. Liu, Invest. New Drugs, 2007, 25, 95.
5. (a) G. Solladié, P. Hugele, R. Bartsch and A. Skoulios, Angew. Chem., Int. Ed., 1996, 35, 1533; (b) D. Yang, M.-K. Wong, Y.-C. Yip, X.-C. Wang, M. W. Tang, J.-H. Zheng and K.-K. Cheung, J. Am. Chem. Soc., 1998, 120, 5943; (c) Y. Uozumi, K. Kato and T. Hayashi, J. Am. Chem. Soc., 1997, 119, 5063; (d) M. B. Andrus, D. Asgari and J. A. Sclafani, J. Am. Chem. Soc., 1997, 62, 9365.
6. (a) M. Takahashi, T. Ogiku, K. Okarnura, T. Da-te, H. Ohrnizu, K. Kondo and T. Iwasaki, J. Chem. Soc., Perkin Trans. 1, 1993, 1473; (b) M. Takahashi, Y. Moritani, T. Ogiku, H. Ohmizu, K. Kondo and T. Iwasaki, Tetrahedron Lett., 1992, 33, 5103; (c) M. Takahashi, T. Kuroda, T. Ogiku, H. Ohmizu, K. Kondo and T. Iwasaki, Tetrahedron Lett., 1991, 32, 6919; (d) S. Miyano, H. Fukushima, S. Handa, H. Ito and H. Hashimoto, Bull. Chem. Soc. Jpn., 1988, 61, 3249; (e) D. M. Hall and J. M. Insole, J. Chem. Soc., Perkin Trans. 2, 1972, 1164.
7. J. A. Corran and W. B. Whalley, J. Chem. Soc., 1958, 4719.
8. (a) S. Kang, S. Lee, M. Jeon, S. M. Kim, Y. S. Kim, H. Han and J. W. Yang, Tetrahedron Lett., 2013, 54, 373; (b) É. Balogh-Hergovich, G. Speier and Z. Tyeklár, Synthesis, 1982, 731; (c) O. Kruber and A. Raeithel, Chem. Ber., 1954, 87, 1469; (d) B. M. Benjamin and C. J. Collins, J. Am. Chem. Soc., 1953, 75, 402; (e) O. Kruber and A. Marx, Chem. Ber., 1938, 71, 2478; (f) J. Schmidt and G. Ladner, Chem. Ber., 1904, 37, 3571.
9. T. Hattori, N. Koike and S. Miyano, J. Chem. Soc., Perkin Trans. 1, 1994, 2273.
10. For recent reviews on aryl–aryl bond formation, see: (a) I. Hussain and T. Singh, Adv. Synth. Catal., 2014, 356, 1661; (b) F. W. Patureau, J. Wencel-Delord and F. Glorius, Aldrichimica Acta, 2012, 45, 31; (c) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (d) S.-L. You and J.-B. Xia, Top. Curr. Chem., 2010, 292, 165; (e) L. Ackermann and R. Vicente, Top. Curr. Chem., 2010, 292, 211; (f) J. A. Ashenhurst, Chem. Soc. Rev., 2010, 39, 540; (g) G. P. McGlacken and L. M. Bateman, Chem. Soc. Rev., 2009, 38, 2447.
11. J. Wencel-Delord, C. Nimphius, F. W. Patureau and F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 2247.
12. H. Gong, H. Zeng, F. Zhou and C.-J. Li, Angew. Chem., Int. Ed., 2015, 54, 5718.
13. J. Wencel-Delord, C. Nimphius, F. W. Patureau and F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 2247.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra21185b

---