Ru-Catalyzed selective C–H oxidative olefination with N-heteroarenes directed by pivaloyl amide

Abstract

A highly efficient and practical Ru-catalyzed direct C–H functionalization of indolines and N-alkylaniline with a simple pivaloyl as a directing group is developed. Broad substrate scopes with respect to N-heteroarenes and olefins are observed. The selective C7-position alkynylation for indoline also proceeds well by using inexpensive ruthenium as a catalyst, and pivaloyl as a directing group.

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Introduction

The nitrogen-containing scaffolds are especially important as they are the omnipresent component in various natural compounds and biologically active products, pharmaceutical compounds and organic dyes.¹ Among these kinds of compounds, the indoline-based alkaloids and aniline derivatives are ubiquitous structural motifs which can be found in various active compounds.² Thus, highly regioselective direct functionalization of these compounds would be highly important and is in great demand. Therefore, a great number of approaches have been developed to functionalize these compounds in the last few decades.³ For example, the selective oxidative coupling of NH-acetanilides with olefins via Pd- and Rh-catalysts has been well explored.^4,5 The group of Carretero reported a general method for the ortho-olefination of N-alkyl aniline derivatives with the 2-pyridylsulfonyl group as the directing group with palladium as a catalyst.⁶ Recently, the selective C–H functionalization of the C-7 position of indoline derivatives has been disclosed by employing a transition-metal-catalyst.⁷ Various coupling partners were successfully employed in these directing group assisted C–H functionalizations, such as alkenylation,⁸ arylation,⁹ alkynylation,¹⁰ allylation,¹¹ amination,¹² alkylation¹³etc. Even though these protocols have emerged, the development of the selective functionalization of the C7-position of indolines or N-alkyl aniline derivatives with less expensive oxidants and cheaper catalysts is still in great demand. Herein we report an oxidative coupling of pivaloyl amide protected indolines and N-alkyl aniline derivatives with olefins via the ruthenium catalyst under mild conditions. Various olefins including acrylates, sulfones, acrylonitriles, phosphonates, vinyl ketones, and allyl alcohols could all tolerate this, affording the corresponding products in moderate to excellent yields.

The highly regioselective C–H transformation with the ruthenium complex as a catalyst was first discovered by Oi and Inoue.¹⁴ Since then, various research groups, such as the groups of Miura,¹⁵ Ackermann,¹⁶ Wang,¹⁷ Dixneuf,¹⁸ Jeganmohan,¹⁹ Ramana,²⁰ and Lam,²¹ have done intensive studies on the ruthenium catalyzed C–H functionalization reactions. Thus, a great number of C–H transformations with various substrates, such as carboxylic acid,²² heterocycle,²³ amide,²⁴ alcohol,²⁵etc., were successfully achieved with the ruthenium catalyst. Inspired by these ruthenium-catalyzed C–H transformations, we speculated that the selective olefination of the C7-position of indolines might be realizable by using the inexpensive and stable ruthenium as the catalyst with well explored pivaloyl amide as the directing group. The ortho-olefination of the pivaloyl group protected N-alkylaniline, of which there are few reports of realizing the ortho-C–H functionalization might also be compatible.

Results and discussion

With these conditions in mind, we first treated pivaloyl amide protected indoline 1a with ethyl acrylate 2a in the presence of [RuCl₂(p-cymene)]₂ (5 mol%), AgSbF₆ (20 mol%), and Cu(OAc)₂·H₂O (1 equiv.) in toluene at 100 °C for 20 h under Ar, the C7-position olefinated product 3a was observed in 7% yield (Table 1, entry 2). We next explored the solvent effect in this oxidative olefination reaction. The solvents including dioxane, acetonitrile, dichloroethane, dichlorideethane, and tert-amyl alcohol (t-AmOH), gave the product 3a in poor results (entries 1–7). Delightfully, tetrahydrofuran showed a great promoting effect in the transformation, affording the desired product 3a in 80% yield (entry 9). We next explored various oxidants to replace the equivalent oxidant copper acetate. However, none of the oxidants could give better results for 3a. When we decreased the reaction temperature to 80 °C, only 63% yield of 3a was achieved (entry 8). Further scanning of the other additives suggested that AgSbF₆ was the best catalyst activating agent. The confirming reaction revealed that the ruthenium catalyst is irreplaceable in this transformation. Notably, alternative directing groups or protecting groups, such as Ac, N-benzoyl, dimethylcarbamyl amide and oxalyl amide were also tested under optimized conditions. However, none could give the corresponding products in more than 20% yield.

Table 1 Optimization of the reaction conditions^a

Entry	Additive	Solvent	T	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [RuCl2(p-cymene)]2 (5 mol%), Cu(OAc)2·H2O (1 equiv.), additive (20 mol%), solvent (1 mL), 100 °C, 20 h, Ar. b GC yield of 3a was determined using tridecane as an internal standard. c Isolated yield. d Cu(OAc)2·H2O (0.2 equiv.). e O2 as the oxidant. f No catalyst.
1	AgSbF6	Dioxane	100 °C	18
2	AgSbF6	Toluene	100 °C	7
3	AgSbF6	DME	100 °C	27
4	AgSbF6	t-AmOH	100 °C	20
5	AgSbF6	CH3CN	100 °C	12
6	AgSbF6	H2O	100 °C	16
7	AgSbF6	DCE	100 °C	32
8	AgSbF6	THF	80 °C	63
9	AgSbF6	THF	100 °C	80 (78)^c
10	AgSbF6	THF	100 °C	21^d (<5)^e
11	AgBF4	THF	100 °C	7
12	None	THF	100 °C	<5
13^f	AgSbF6	THF	100 °C	0

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Next, we started to explore the substrate scope of N-heteroarenes under the optimized simple reaction conditions (Table 2). The pivaloyl-protected 2-methylindoline gave the olefinated product 3b in excellent yield. However, a stronger electron-withdrawing substituent afforded lower yield under the standard reaction conditions (3c, 3d). The six-membered N-heteroarenes including 1,2,3,4-tetrahydroquinoline and benzomorpholine were also tested under the optimized reaction conditions, affording the corresponding products in good yields (3e, 3f, 3g). Encouraged by the observed results, we next expanded the substrates to N-alkylaniline, which has few approaches to realize the ortho-C–H functionalization. The simple pivaloyl amide exhibited excellent coordination ability with the ruthenium catalyst to perform the oxidative C–H/C–H olefination. Generally, the steric effect greatly affected the transformation. For example, the less hindered functional groups of methyl, ethyl, and n-butyl gave the corresponding olefinated products in good yields respectively (3h, 3i, 3k). The bulk function groups of isopropyl and benzyl afforded the corresponding products in less than 50% yield (3m, 3j), along with the recovery of the starting material. The ortho, meta, and para substituted N-methylaniline all transformed into olefinated products in good yield.

Table 2 Substrate scope of N-alkylaniline^a

a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [RuCl₂(p-cymene)]₂ (5 mol%), Cu(OAc)₂·H₂O (1 equiv.), additive (20 mol%), THF (1 mL), 100 °C, 20 h, Ar. b 120 °C, 24 h.

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Subsequently, the scope of olefins was examined and the results are listed in Table 3. Generally, the acrylates gave the corresponding olefinated products in good yields (3s, 3t, 3u). Interestingly, both electron rich and deficient olefins could undergo oxidative olefination, selectively affording the products. The results indicated that the electron-deficient olefins are more active than the electron-rich olefins. Further scanning revealed that the other electron-deficient olefins including sulfones, acrylonitriles, phosphonates, and vinyl ketones all proceed well, affording the corresponding products in good to excellent yields (3w, 3x, 3z). Impressively, the allyl alcohol 2h successfully participated in the oxidative olefination reaction, providing 3y in 68% yield. It was probable that the oxidant copper acetate could oxidize the alcohol to ketone during the reaction. Interestingly, allyl acetate could be used as a coupling partner, which gave a quaint olefinated product in good yield (3aa).

Table 3 Substrate scope of olefins^a

Entry	2	3 products	Yield (%)
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), [RuCl2(p-cymene)]2 (5 mol%), Cu(OAc)2·H2O (1 equiv.), AgSbF6 (20 mol%), THF (1 mL), 100 °C, 20 h, Ar.
1			72
2			74
3			73
4			75
5			89
6			91
7			68
8			81
9			78

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To further demonstrate the synthetic utility of this developed method, gram scale reactions were performed with less amount of catalyst, and an excellent yield of 3a was achieved. As expected, the product could be transformed into indole derivatives in quantitative yield. Finally the pivaloyl directing group could be easily removed under basic conditions, providing the C7-position olefinated product 3ac in 89% yield (Scheme 1).

Scheme 1 Gram scale reaction and synthetic indole derivatives.

Alkynes are attractive building blocks in synthetic chemistry due to their versatile transformation in the synthesis of multiple functional groups. To the best of our knowledge, there is still no report of the selective alkynylation of the C7 position of indolines with the ruthenium catalyst. To our great delight, the alkynylation could be realized in good yields by using H₂O as the solvent and KPF₆ as the additive, which meets the requirement of green chemistry. Unfortunately, the alkynylation was not compatible with pivaloyl protected N-alkylaniline substrates (Scheme 2).

Scheme 2 Synthetic alkynylation of indoline derivatives.

Based on previous reports,²⁶ a plausible mechanism for this oxidative olefination is shown in Scheme 3. First, the [RuCl₂(p-cymene)]₂ catalyst is activated by Ag⁺ in the reaction. The ruthenium species coordinated with the pivaloyl directing group, followed by ortho metalation, affording a six-membered metallacycle intermediate I. Regioselective coordinative insertion of olefin into the ruthenium complex provides the intermediate II. Subsequent reductive elimination and β-hydride elimination, generates the olefinated product. The ruthenium complex could be further oxidized to active the ruthenium species with copper acetate as the oxidant.

Scheme 3 Proposed mechanism.

Conclusions

In summary, we have developed a practical and highly efficient Ru-catalyzed selective C–H functionalization of indolines and N-alkylaniline with a simple pivaloyl as a directing group. Various substrate scopes with respect to N-heteroarenes and olefins are achieved. The C7-position alkynylation is also realized with ruthenium as a catalyst. Further studies on the mechanism are currently underway in our lab.

Acknowledgements

This research was supported financially by the Natural Science Foundation of China (no. 21572149) and the Young National Natural Science Foundation of China (no. 21403148). The support of PAPD is also greatly acknowledged.

Notes and references

1. (a) J. P. Burke, Z. Bian, S. Shaw, B. Zhao, C. M. Goodwin, J. Belmar, C. F. Browning, D. Vigil, A. Friberg, D. V. Camper, O. W. Rossanese, T. Lee, E. T. Olejniczak and S. W. Fesik, J. Med. Chem., 2015, 58, 3794; (b) Y. Ozawa, K. Kusano, T. Owa, A. Yokoi, M. Asada and K. Yoshimatsu, Cancer Chemother. Pharmacol., 2012, 69, 1353; (c) A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489; (d) B. M. Trost and M. K. Brennan, Synthesis, 2009, 3003; (e) P. Dydio, T. Zielinski and J. Jurczak, Chem. Commun., 2009, 30, 4560; (f) Y. Ferandin, K. Bettayeb, M. Kritsanida, O. Lozach, P. Polychronopoulos, P. Magiatis, A.-L. Skaltsounis and L. Meijer, J. Med. Chem., 2006, 49, 4638; (g) R. Hili and A. K. Yudin, Nat. Chem. Biol., 2006, 2, 284; (h) R. Mohan, M. Banerjee, A. Ray, T. Manna, L. Wilson, T. Owa, B. Bhattacharyya and D. Panda, Biochemistry, 2006, 45, 5440; (i) F.-E. Chen and J. Huang, Chem. Rev., 2005, 105, 4671; (j) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893; (k) D. L. Boger, C. B. Boyce, R. M. Garbaccio and J. A. Goldberg, Chem. Rev., 1997, 97, 787.
2. (a) C. Ma, X. Yang, H. Kandemir, M. Mielczarek, E. B. Johnston, R. Griffith, N. Kumar and P. J. Lewis, ACS Chem. Biol., 2013, 8, 1972; (b) B. M. Trost and M. K. Brennan, Synthesis, 2009, 3003; (c) Z. Wang and R. Vince, Bioorg. Med. Chem., 2008, 16, 3587; (d) M. G. Bell, D. L. Gernert, T. A. Grese, M. D. Belvo, P. S. Borromeo, S. A. Kelley, J. H. Kennedy, S. P. Kolis, P. A. Lander, R. Richey, V. S. Sharp, G. A. Stephenson, J. D. Williams, H. Yu, K. M. Zimmerman, M. I. Steinberg and P. K. Jadhav, J. Med. Chem., 2007, 50, 6443; (e) C. B. Hartline, E. A. Harden, S. L. Williams- Aziz, N. L. Kushner, R. J. Brideau and E. R. Kern, Antiviral Res., 2005, 65, 97; (f) B. Meseguer, D. Alonso-Díaz, N. Griebenow, T. Herget and H. Waldmann, Angew. Chem., Int. Ed., 1999, 38, 2902; (g) D. R. Beukes, M. T. Davie- Coleman, M. Kelly-Borges, M. K. Harper and D. J. Faulkner, J. Nat. Prod., 1998, 61, 699; (h) D. L. Boger, C. W. Boyce, R. M. Garbaccio and J. A. Goldberg, Chem. Rev., 1997, 97, 787; (i) K. Mahmood, M. Pais, C. Fontaine, H. M. Ali, A. H. A. Hadi and E. Gulttet, Tetrahedron Lett., 1993, 34, 1795.
3. (a) S. Pan, T. Wakaki, N. Ryu and T. Shibata, Chem. – Asian J., 2014, 9, 1257; (b) L.-Y. Jiao and M. Oes-treich, Chem. – Eur. J., 2013, 19, 10845; (c) L.-Y. Jiao and M. Oestreich, Org. Lett., 2013, 15, 5374; (d) Z. Song, R. Samanta and A. P. Antonchick, Org. Lett., 2013, 15, 5662; (e) S. De, S. Ghosh, S. Bhunia, J. A. Sheikh and A. Bisai, Org. Lett., 2012, 14, 4466.
4. (a) P. Kannaboina, K. A. Kumar and P. Das, Org. Lett., 2016, 5, 900; (b) D. Yang, S. Mao, Y.-R. Gao, D.-D. Guo, S.-H. Guo, B. Li and Y.-Q. Wang, RSC Adv., 2015, 5, 23727; (c) L.-Y. Jiao and M. Oestreich, Org. Lett., 2013, 15, 5374; (d) L.-Y. Jiao and M. Oestreich, Chem. – Eur. J., 2013, 19, 10845; (e) T. Nishikata and B. H. Lishutz, Org. Lett., 2010, 12, 1972; (f) W. Rauf, A. L. Thompson and J. M. Brown, Chem. Commun., 2009, 26, 3874.
5. (a) Z. Song, R. Samanta and A. P. Antonchick, Org. Lett., 2013, 15, 5662; (b) F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 2010, 132, 9982; (c) J. Willwacher, S. Rakshit and F. Glorius, Org. Biomol. Chem., 2011, 9, 4736.
6. A. García-Rubia, B. Urones, R. G. Arrayás and J. C. Carretero, Angew. Chem., Int. Ed., 2011, 50, 10921.
7. (a) W. Hou, Y. Yang, W. Ai, Y. Wu, X. Wang, B. Zhou and Y. Li, Eur. J. Org. Chem., 2015, 395; (b) C. Pan, A. Abdukader, J. Han, Y. Cheng and C. Zhu, Chem. – Eur. J., 2014, 20, 3606; (c) T. Nishikata, A. R. Abela, S. Huang and B. H. Lip-shutz, J. Am. Chem. Soc., 2010, 132, 4978; (d) Z. Shi, B. Li, X. Wan, J. Cheng, Z. Fang, B. Cao, C. Qin and Y. Wang, Angew. Chem., Int. Ed., 2007, 46, 5554; (e) D. Kalyani, N. R. Deprez, L. V. Desai and M. S. Sanford, J. Am. Chem. Soc., 2005, 127, 7330.
8. (a) X.-F. Yang, X.-H. Hu, C. Feng and T.-P. Loh, Chem. Commun., 2015, 51, 2532; (b) D. Yang, S. Mao, Y.-R. Gao, D.-D. Guo, S.-H. Guo, B. Li and Y.-Q. Wang, RSC Adv., 2015, 5, 23727; (c) S. Pan, T. Wakaki, N. Ryu and T. Shibata, Chem. – Asian J., 2014, 9, 1257; (d) B. Urones, R. G. Arrayás and J. C. Carretero, Org. Lett., 2013, 15, 1120; (e) L. Jiao and M. Oestreich, Org. Lett., 2013, 15, 5374; (f) Z. Song, R. Samanta and A. P. Antonchick, Org. Lett., 2013, 15, 5662.
9. (a) L.-Y. Jiao, P. Smirnov and M. Oestreich, Org. Lett., 2014, 16, 6020; (b) L. Jiao and M. Oestreich, Chem. – Eur. J., 2013, 19, 10845; (c) T. Nishikata, A. R. Abela, S. Huang and B. H. Lipshutz, J. Am. Chem. Soc., 2010, 132, 4978; (d) D. Kalyani, N. R. Deprez, L. V. Desai and M. S. Sanford, J. Am. Chem. Soc., 2005, 127, 7330; (e) Z. Shi, B. Li, X. Wan, J. Cheng, Z. Fang, B. Cao, C. Qin and Y. Wang, Angew. Chem., Int. Ed., 2007, 46, 5554.
10. (a) Y.-X. Wu, Y.-X. Yang, B. Zhou and Y.-C. Li, J. Org. Chem., 2015, 80, 1946; (b) X.-F. Yang, X.-H. Hu, C. Feng and T.-P. Loh, Chem. Commun., 2015, 51, 2532.
11. (a) S. Sharma, Y. Shin, N. K. Mishra, J. Park, S. Han, T. Jeong, Y. Oh, Y. Lee, M. Choi and I. S. Kim, Tetrahedron, 2015, 71, 2435; (b) J. Park, N. K. Mishra, S. Sharma, S. Han, Y. Shin, T. Jeong, J. S. Oh, J. H. Kwak, Y. H. Jung and I. S. Kim, J. Org. Chem., 2015, 80, 1818; (c) M. Kim, S. Sharma, N. K. Mishra, S. Han, J. Park, M. Kim, Y. Shin, J. H. Kwak, S. H. Han and I. S. Kim, Chem. Commun., 2014, 50, 11303.
12. (a) K. Shinand and S. Chang, J. Org. Chem., 2014, 79, 12197; (b) C. Pan, A. Abdukader, J. Han, Y. Cheng and C. Zhu, Chem. – Eur. J., 2014, 20, 3606; (c) W. Hou, Y. Yang, W. Ai, Y. Wu, X. Wang, B. Zhou and Y. Li, Eur. J. Org. Chem., 2015, 395; (d) J. Kim, J. Kim and S. Chang, Chem. – Eur. J., 2013, 19, 7328; (e) M. R. Yadav, R. K. Rit and A. K. Sahoo, Org. Lett., 2013, 15, 1638.
13. (a) S. Pan, S. Ryu and T. Shibata, Adv. Synth. Catal., 2014, 356, 929; (b) W. Ai, X.-Y. Yang, Y.-X. Wu, X. Wang, Y.-C. Li, Y.-X. Yang and B. Zhou, Chem. – Eur. J., 2014, 20, 17653; (c) S. R. Neufeldt, C. K. Seigerman and M. Sanford, Org. Lett., 2013, 15, 2302.
14. S. Oi, Y. Tanaka and Y. Inoue, Organometallics, 2006, 25, 4773.
15. (a) Y. Hashimoto, T. Ortloff, K. Hirano, T. Satoh, C. Bolm and M. Miura, Chem. Lett., 2012, 41, 151; (b) T. Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2011, 13, 706.
16. (a) J. Li, C. Kornhaaß and L. Ackermann, Chem. Commun., 2012, 48, 11343; (b) L. Ackermann, L. Wang, R. Wolfram and A. V. Lygin, Org. Lett., 2012, 14, 728; (c) K. Graczyk, W. Ma and L. Ackermann, Org. Lett., 2012, 14, 4110; (d) L. Ackermann, L. H. Wang, R. Wolfram and A. V. Lygin, Org. Lett., 2011, 14, 728; (e) L. Ackermann and J. Pospech, Org. Lett., 2011, 13, 4153.
17. (a) B. Li, J. Ma, Y. Liang, N. Wang, S. Xu, H. Song and B. Wang, Eur. J. Org. Chem., 2013, 1950; (b) B. Li, J. F. Ma, H. B. Song, S. S. Xu and B. Q. Wang, J. Org. Chem., 2013, 78, 9345.
18. (a) K. S. Singh and P. H. Dixneuf, Organometallics, 2012, 31, 7320; (b) P. B. Arockiam, C. Fischmeister, C. Bruneau and P. H. Dixneuf, Green Chem., 2011, 13, 3075.
19. (a) K. Padala and M. Jeganmohan, Org. Lett., 2012, 14, 1134; (b) K. Padala and M. Jeganmohan, Org. Lett., 2011, 13, 6144.
20. Y. Goriya and C. V. Ramana, Chem. – Eur. J., 2012, 18, 3288.
21. S. R. Chidipudi, M. D. Wieczysty, I. Khan and H. W. Lam, Org. Lett., 2013, 15, 570.
22. (a) L. Ackermann and J. Pospech, Org. Lett., 2011, 13, 4153; (b) K. Padala, S. Pimparkar, P. Madasamy and M. Jeganmohan, Chem. Commun., 2012, 48, 7140; (c) R. K. Chinnagolla and M. Jeganmohan, Chem. Commun., 2012, 48, 2030.
23. (a) C. Tirler and L. Ackermann, Tetrahedron, 2015, 71, 4543; (b) N. Hofmann and L. Ackermann, J. Am. Chem. Soc., 2013, 135, 5877; (c) J. Li, S. Warratz, D. Zell, S. D. Sarkar, E. E. Ishikawa and L. Ackermann, J. Am. Chem. Soc., 2015, 137, 13894; (d) L. Ackermann, R. Vicente, H. K. Potukuchi and V. Pirovano, Org. Lett., 2010, 12, 5032.
24. (a) C. S. Kuai, L. H. Wang, H. Y. Cui, J. H. Shen, Y. D. Feng and X. L. Cui, ACS Catal., 2016, 6, 186; (b) J. C. Wu;, W. B. Xu, Z.-X. Yu and J. Wang, J. Am. Chem. Soc., 2015, 137, 9489.
25. (a) L. Ackermann, J. Pospech and H. K. Potukuchi, Org. Lett., 2012, 14, 2146; (b) V. S. Thirunavukkarasu, M. Donati and L. Ackermann, Org. Lett., 2012, 14, 3417.
26. (a) H. J. Li, X. Y. Xie and L. Wang, Chem. Commun., 2014, 50, 4218; (b) Q.-Z. Zheng, Y.-F. Liang, C. Qin and N. Jiao, Chem. Commun., 2013, 49, 5654; (c) K. Padala and M. Jeganmohan, Org. Lett., 2011, 13, 6144; (d) C. D. Pan, A. Abdukader, J. Han, Y. X. Cheng and C. J. Zhu, Chem. – Eur. J., 2014, 20, 3606.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00327c

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