Palladium-catalyzed direct ortho C–O bond construction of azoxybenzenes with carboxylic acids and alcohols

Abstract

A Pd(II) catalyzed C–O bond formation of azoxybenzenes has been developed. An N-atom served as a directing group, as confirmed by the single crystal X-ray diffraction analysis of the palladium complex. The products were obtained in moderate to excellent yields for 29 examples. This protocol features high regioselectivity, wide functional group tolerance and atom economy.

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Introduction

Azoxybenzenes are widely applied in pharmaceuticals,^1a oxidants,^1b–d photochemistry,^1e spectroscopy,^1f,g polymer inhibitors and stabilizers.^1h In light of their importance, the development of azoxybenzene derivatives has been a hot topic. Nowadays direct C–H bond functionalization has been established to build various azoxybenzene derivatives. The transition-metal-catalyzed ortho-halogenation,²ortho-acylation,³ortho-arylation,⁴ortho-alkoxylation,⁵ortho-acyloxyation,⁶ortho-amidation,⁷ortho-sulfonylation,⁸ortho-phosphorylation,⁹ortho-nitration¹⁰ and cyclization¹¹ of azobenzenes have been developed rapidly. Compared with the formation of C–C, C–S and C–N bonds, the reports on the C–O bond formation based metal-catalyzed C–H bonds activation are less well established, maybe due to the electronegativities of the oxygen atom as well as its strong coordination with metals.^5a,12 To the best of our knowledge, there are only three examples of building the C–O bond of azobenzenes in the literature as shown in Scheme 1. Acyloxyation of the azobenzene was reported by the Sanford^6a and Cárdenas groups^6bvia palladium-catalyzed C–H acyloxyation of azobenzene with PhI(OAc)₂ and Zeng^6d obtained the acyloxylated azobenzene via palladium-catalyzed acyloxyation of azobenzene with aryl acylperoxides. Sun^5a presented alkoxylation of the azobenzene via palladium-catalyzed alkoxylation of azobenzene with methanol. Additionally, the previous studies by Wang,¹³ Zang¹⁴ and our group¹⁵ indicated that the introduction of an azoxy group into the azobenzenes can not only bring about a high regioselectivity, but also enhance the reactivity of the target C–H bond. In continuation of our effort on C–H functionalization of azoxybenzenes, we embark on the development of a simple and efficient procedure for various acyloxyazoxybenzenes and alkoxylazoxybenzenes based on palladium-catalyzed direct C–H bond activation with high efficiency and regioselectivity under mild conditions. Compared to azobenzenes, azoxybenzenes exhibited higher regioselectivity and resulted in milder reaction conditions.

Scheme 1 Palladium-catalyzed direct C–O bond construction of diazobenzenes.

Results and discussion

Initially, the cross-coupling of azoxybenzene 1a and acetic acid 2a was chosen as a model reaction to screen various reaction parameters. The results are summarized in Table 1. When the reaction was carried out in carboxylic acids at 100 °C with 10 mol% Pd(OAc)₂ as a catalyst and K₂S₂O₈ (2.0 equiv.) as an oxidant, the desired o-acyloxyazoxybenzene 3a was afforded in 79% yield (entry 1, Table 1). Subsequently, a further screening of Pd(dba)₂, PdCl₂, and Pd(TFA)₂ salts indicated that Pd(TFA)₂ was the best catalyst and could provide 3a in 86% yield (entries 1–4, Table 1). Other oxidants, such as TBHP, DTBP, Ag₂CO₃, AgNO₃, Ag₂O and AgOAc, turned out to be inferior to K₂S₂O₈ (entries 5–10, Table 1). When prolonging the reaction time to 10 hours, the yield was not improved significantly (entry 11, Table 1). The catalyst loading was reduced to 2.5 mol% and the reaction time was 14 hours, the product 3a was obtained in 86% yield (entry 12, Table 1). After surveying the reaction parameters, the optimal reaction conditions were determined as follows: azoxybenzene (0.2 mmol), Pd(TFA)₂ (2.5 mol%), and K₂S₂O₈ (2.0 equiv.) in acetic acid (2.0 ml) in a 100 °C oil bath under air for 14 hours.

Table 1 Optimizing reaction conditions for the Pd-catalyzed cross-coupling of azoxybenzene 1a with acetic acid 2a^a

Entry	Catalyst	Oxidant	Time	Yield^b %
a Reaction conditions: azoxybenzene (1a) (0.2 mmol), acetic acid (2a) (2.0 ml), catalyst (10 mol%), oxidant (2.0 equiv.), under air, 100 °C. b Isolated yield based on 1a. c Pd(TFA)2 (2.5 mol%).
1	Pd(OAc)2	K2S2O8	6 h	79
2	Pd(dba)2	K2S2O8	6 h	16
3	Pd(Cl)2	K2S2O8	6 h	7
4	Pd(TFA)2	K2S2O8	6 h	86
5	Pd(TFA)2	TBHP	6 h	nr
6	Pd(TFA)2	DTBP	6 h	nr
7	Pd(TFA)2	AgNO3	6 h	Trace
8	Pd(TFA)2	Ag2CO3	6 h	nr
9	Pd(TFA)2	Ag2O	6 h	nr
10	Pd(TFA)2	AgOAc	6 h	nr
11	Pd(TFA)2	K2S2O8	10 h	89
12^c	Pd(TFA)2	K2S2O8	14 h	86

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The alkoxylation of azoxybenzene with alcohols was investigated. By changing the coupling partner to methanol, methoxyazoxybenzene was achieved in 22% yield (entry 1, Table 2). When the loading of Pd(TFA)₂ was increased to 10 mol%, product 4a was obtained in 34% yield (entry 2, Table 2). Inspired by the previous studies, suitable additives might bring crucial effects on the C–H bond activation.¹⁶ When 1.2 mmol (6.0 equiv.) of CF₃COOH were added, the yield was improved to 50% (entry 3, Table 2). Compared to K₂S₂O₈, PhI(OAc)₂ was better (entry 3 vs. entry 4, Table 2). To our surprise, when the reaction occurred at room temperature, the yield was not significantly changed (entry 5, Table 2). When the TFA loading was increased to 12.0 equiv. and 18.0 equiv., product 4a was obtained in 73% and 80% yields, respectively (entries 6 and 7, Table 2). So, the optimal reaction conditions were determined: azoxybenzene (0.2 mmol), Pd(TFA)₂ (10 mol%), K₂S₂O₈ (2.0 equiv.), and TFA (18.0 equiv.) in methanol (2.0 ml) at room temperature under air for 20 hours.

Table 2 Optimizing reaction conditions for the Pd-catalyzed cross-coupling of azoxybenzene 1a and methanol^a

Entry	Oxidant	Additive	T	Yield^b %
a Reaction conditions: azoxybenzene (1a) (0.2 mmol), MeOH (2a′) (2.0 ml), Pd(TFA)2 (10 mol%), oxidant (2.0 equiv.), under air, 20 h. b Isolated yield based on 1a. c Pd(TFA)2 (2.5 mol%). d Room temperature.
1^c	K2S2O8	None	100	22
2	K2S2O8	None	100	34
3	K2S2O8	TFA (6.0 equiv.)	100	50
4	PhI(OAc)2	TFA (6.0 equiv.)	100	57
5^d	PhI(OAc)2	TFA (6.0 equiv.)	R.T.	58
6^d	PhI(OAc)2	TFA (12.0 equiv.)	R.T.	73
7^d	PhI(OAc)2	TFA (18.0 equiv.)	R.T.	80

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With the optimized reaction conditions in hand, the scope of the reaction between azoxybenzene and carboxylic acids was assessed under the optimized conditions (Table 1). A variety of linear carboxylic acids could be coupled with azoxybenzene (1a), affording the ortho-acyloxyation of azoxybenzenes in 47–86% yields (3a–3e, Scheme 2). The carboxylic acids with α or β steric hindrances were suitable substrates. For example, isovaleric acid, isobutyric acid and trimethylacetic acid gave the corresponding products in 65%, 62% and 44% yields, respectively (3f–3h, Scheme 2). Next, we explored the azoxybenzenes substrates, and found that the procedure can be widely applied. The 2,2′-dimethyl could promote this reaction and give the desired products in 97% yield (3i, Scheme 2). While the 3,3′-dimethyl azoxybenzene provided the product in 65% yield and 3,3′-dibromo azoxybenzene provided the product in 30% yield (3j–3k, Scheme 2). The successful conversion of 4,4′-difluoro, 4,4′-dichloro, 4,4′-ditrifluoromethoxy and 4,4′-diisopropyl azoxybenzenes showed that electron-withdrawing and electron-donating groups substituted in substrates are tolerated (3l–3o, Scheme 2). It is worthy of note that these standard reaction conditions were applied to the unsymmetrical azoxybenzene, affording the corresponding product with only one isomer in 77% yield (3p, Scheme 2). When the 4,4′-dimethyl azoxybenzene reacted with propionic acid, 38% yield was obtained (3q, Scheme 2). The structure of 3q was confirmed by single crystal X-ray diffraction and shown in Fig. 1 in the ESI.†

Scheme 2 The scope of palladium-catalyzed ortho C–O formation of azoxybenzenes with carboxylic acids. Reaction conditions: azoxybenzenes (0.2 mmol), Pd(TFA)₂ (2.5 mol%), K₂S₂O₈ (2.0 equiv.), carboxylic acids (2.0 ml), 100 °C, under air for 14 hours. Isolated yield.

A similar rule applies to azoxybenzene (1a) coupled with alcohols. A variety of linear or branched alcohols could react with azoxybenzenes (1a) to give products 4a–4g. Linear alcohols, such as methanol, ethanol, propanol, butanol and hexylalcohol could be coupled well with azoxybenzene (1a), affording products in 41–80% yields (4a–4e, Scheme 3). The branched alcohols with the steric hindrance of isobutanol and isopropanol did not significantly affect this transformation, providing the desired products in 38% and 34% yields (4f–4g, Scheme 3). Moreover, the steric effect was observed when methyl-substituted azoxybenzenes at their ortho-, meta- and para-positions were also suitable substrates and successfully afforded the desired products in 94%, 81% and 54% yields, respectively (4h–4j, Scheme 3). The more electron-donating the groups on the para-positions, the lower the yield obtained (4jvs.4kScheme 3). As an unsymmetrical substrate, 2-OCH₃ azoxybenzene also proceeded well with excellent regioselectivity and gave the product in 79% yield (4lScheme 3). The structure of 4l was confirmed by single crystal X-ray diffraction and shown in Fig. 1 in the ESI.†

Scheme 3 The scope of palladium catalyzed ortho C–O formation of azoxybenzenes with alcohols. Reaction conditions: azoxybenzenes (0.2 mmol), alcohols (2.0 ml), Pd(TFA)₂ (10 mol%), PhI(OAc)₂ (2.0 equiv.), TFA (18.0 equiv.), room temperature, under air for 20 h. Isolated yield.

To clarify the reaction mechanism, 4.0 equiv. of TEMPO was added to the reactions under the optimized conditions, respectively and no desirable products were detected. Therefore, it suggested that these reactions involve a free radical pathway (Scheme 4). Although the details of the mechanism of this C–O formation remain to be elucidated, a possible mechanism is outlined based on the earlier literature and our preliminary studies.¹⁷ The nitrogen atom in azoxybenzene 1a firstly reacted with Pd(TFA)₂ to form palladacycle complex I (Fig. 1) through the ortho-C–H bond activation, which accounted for the high regioselectivity in the reactions. Next, the palladium(II) intermediate was reacted with the alkoxyl radical¹⁸ or carbonyl oxygen radicals^6d,19 to form a palladium(III) or palladium(IV) complex II.²⁰ The reductive elimination of complex II gave the C–O coupled product accompanied by the regeneration of the palladium(II) catalyst.

Scheme 4 Proposed reaction mechanism.

Fig. 1 The X-ray molecular structures of 3q, 4l and complex I.

Conclusions

In summary, we have developed a Pd(II) catalyzed C–O bond formation of azoxybenzenes with carboxylic acids and alcohols. An N-atom served as a directing group, as confirmed by single crystal X-ray diffraction analysis. Both acyloxyazoxybenzenes and alkoxylazoxybenzenes were obtained smoothly by these processes. This protocol features high regioselectivity, wide functional group tolerance and atom economy. Further investigations to expand the substrate scope and application of such chemistry in organic synthesis are underway.

Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China (21172200) and Zhengzhou University.

Notes and references

1. For applications of azoxybenzenes, see: (a) H. Takahashi, T. Ishioka, Y. Koiso, M. Sodeoka and Y. Hashimoto, Biol. Pharm. Bull., 2000, 23, 1387; (b) V. M. Dziomko and K. A. Dunaevskaya, Zh. Obshch. Khim., 1961, 31, 3385; (c) L. Giuseppe and R. Amerigo, Ann. Chim., 1956, 46, 296; (d) A. F. Worth and L. Kenneth, Trans. Kans. Acad. Sci., 1932, 35, 146; (e) M. Ōkubo, H. Hyakutake and N. Taniguchi, Bull. Chem. Soc. Jpn., 1988, 61, 3005; (f) A. Barth, J. E. T. Corrie, M. J. Gradwell, Y. Maeda, W. Mäntele, T. Meier and D. R. Trentham, J. Am. Chem. Soc., 1997, 119, 4149; (g) M. A. Berwick and R. E. Rondeau, J. Org. Chem., 1972, 37, 2409; (h) J. M. Huang, J. F. Kuo and C. Y. Chen, J. Appl. Polym. Sci., 1995, 55, 1217.
2. X. T. Ma and S. K. Tian, Adv. Synth. Catal., 2013, 355, 337.
3. (a) H. Y. Song, D. Chen, C. Pi, X. L. Cui and Y. J. Wu, J. Org. Chem., 2014, 79, 2955; (b) H. J. Li, P. H. Li, Q. Zhao and L. Wang, Chem. Commun., 2013, 49, 9170; (c) Z. Y. Li, D. D. Li and G. W. Wang, J. Org. Chem., 2013, 78, 10414; (d) F. Xiong, C. Qian, D. E. Lin, W. Zeng and X. X. Lu, Org. Lett., 2013, 15, 5444; (e) H. J. Li, P. H. Li and L. Wang, Org. Lett., 2013, 15, 620; (f) H. Tang, C. Qian, D. E. Lin, H. F. Jiang and W. Zeng, Adv. Synth. Catal., 2014, 356, 519.
4. S. Miyamura, H. Tsurugi, T. Satoh and M. Miura, J. Organomet. Chem., 2008, 693, 2438.
5. (a) Z. W. Yin, X. Q. Jiang and P. P. Sun, J. Org. Chem., 2013, 78, 10002; (b) S. Shi and C. Kuang, J. Org. Chem., 2014, 79, 6105.
6. (a) A. R. Dick, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2004, 126, 2300; (b) F. Tato, A. García-Domínguez and D. J. Cárdenas, Organometallics, 2013, 32, 7487; (c) B. C. Kocher, C. Weder and P. Smith, Adv. Funct. Mater., 2003, 13, 427; (d) C. Qian, D. G. Lin, Y. F. Deng, X. Q. Zhang, H. F. Jiang, G. Miao, X. H. Tang and W. Zeng, Org. Biomol. Chem., 2014, 12, 5866.
7. X. F. Jia and J. Han, J. Org. Chem., 2014, 79, 4180.
8. D. Zhang, X. L. Cui, Q. Q. Zhang and Y. J. Wu, J. Org. Chem., 2015, 80, 1517.
9. G. Hong, D. Mao, S. Y. Wu and L. M. Wang, J. Org. Chem., 2014, 79, 10629.
10. J. W. Dong, B. Jin and P. P. Sun, Org. Lett., 2014, 16, 4540.
11. (a) K. Takagi, M. Al-Amin, N. Hoshiya, J. Wouters, H. Sugimoto, Y. Shiro, H. Fukuda, S. Shuto and M. Arisawa, J. Org. Chem., 2014, 79, 6366; (b) J. Y. Jo, H. Y. Lee, W. J. Liu, A. Olasz, C. H. Chen and D. Lee, J. Am. Chem. Soc., 2012, 134, 16000; (c) D. B. Zhao, Q. Wu, X. L. Huang, F. J. Song, T. Y. Lv and J. S. You, Chem. – Eur. J., 2013, 19, 6239; (d) K. Muralirajan and C. H. Cheng, Chem. – Eur. J., 2013, 19, 6198; (e) A. Alberti, N. Bedogni, M. Benaglia, R. Leardini, D. Nanni, G. F. Pedulli, A. Tundo and G. Zanardi, J. Org. Chem., 1992, 57, 607; (f) X. L. Huang, X. Y. Chen and S. Ye, J. Org. Chem., 2009, 74, 7585; (g) S. S. Mochalov, M. I. Khasanov, A. N. Fedotov and E. V. Trofimova, Chem. Heterocycl. Compd., 2008, 44, 229.
12. (a) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470.
13. (a) H. J. Li, P. H. Li, Q. Zhao and L. Wang, Chem. Commun., 2013, 49, 9170; (b) H. Li, X. Y. Xie and L. Wang, Chem. Commun., 2014, 50, 4218.
14. M. Sun, L. K. Hou, X. X. Chen, X. J. Yang, W. Sun and Y. S. Zang, Adv. Synth. Catal., 2014, 356, 3789.
15. M. L. Yi, X. L. Cui, C. W. Zhu, C. Pi, W. M. Zhu and Y. J. Wu, Asian J. Org. Chem., 2015, 4, 38.
16. (a) B. Xiao, Y. Fu, J. Xu, T. J. Gong, J. J. Dai, J. Yi and L. Liu, J. Am. Chem. Soc., 2010, 132, 468; (b) B. Xiao, T. J. Gong, J. Xu, Z. J. Liu and L. Liu, J. Am. Chem. Soc., 2011, 133, 1466; (c) R. Giri, J. K. Lam and J. Q. Yu, J. Am. Chem. Soc., 2010, 132, 686.
17. (a) X. Chen, K. M. Engle, D. H. Wang and J. Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (b) L. M. Xu, B. J. Li, Z. Yang and Z. J. Shi, Chem. Soc. Rev., 2010, 39, 712; (c) K. M. Engle, T. S. Mei, M. Wasa and J. Q. Yu, Acc. Chem. Res., 2012, 45, 788; (d) V. S. Thirunavukkarasu, S. I. Kozhushkov and L. Ackermann, Chem. Commun., 2014, 50, 29.
18. (a) G. S. Georigiev, E. B. Kamenska, N. V. Tsarevsky and L. K. Christov, Polym. Int., 2001, 50, 313; (b) R. Amorati, L. Valgimigli, P. Dinér, K. Bakhtiari, M. Saeedi and L. Engman, Chem. – Eur. J., 2013, 19, 7510.
19. (a) Y. Siddaraju, M. Lamni and K. R. Prabhu, J. Org. Chem., 2014, 79, 3856; (b) X. Mi, C. Y. Wang, M. M. Huang, Y. S. Wu and Y. J. Wu, J. Org. Chem., 2015, 80, 148.
20. (a) D. C. Powaers, M. A. L. Geibel, J. E. M. N. Klein and T. Ritter, J. Am. Chem. Soc., 2009, 131, 17050; (b) D. C. Powers and T. Ritter, Nat. Chem., 2009, 1, 302; (c) J. M. Racowski, A. R. Dick and M. S. Sanford, J. Am. Chem. Soc., 2009, 131, 10974; (d) N. R. Deprez and M. S. Sanford, J. Am. Chem. Soc., 2009, 131, 11234.

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Footnote

† Electronic supplementary information (ESI) available: Preparation of azoxybenzene, the spectral data for all products and crystallographic data for 3q, 4l and complex I (CIF). CCDC 1030211, 1024177 and 1026842. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00120j

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