Pd(II)-catalyzed β-C–H arylation of O-methyl ketoximes with iodoarenes

Abstract

A Pd(II)-catalyzed selective β-arylation of O-methyl ketoximes was developed using iodoarenes as the coupling partners. This transformation has good functional group compatibility and can serve as a powerful synthetic tool for late-stage C–H arylation of complex compounds. Moreover, when employing 2-iodobenzoic acids as the substrates in this developed catalytic system, a type of unexpected five-membered lactones could be formed by tandem sp³ C–H arylation and oxygenation.

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Zhuangzhi Shi

Zhuangzhi Shi was born in Jiangsu Province in 1983. He received his B.S. and M.S. degrees in chemistry and organic chemistry with Prof. Yu Yuan from Yangzhou University in 2005 and 2008. Then he moved to Peking University and completed his Ph.D. degree in medicinal chemistry under the supervision of Prof. Ning Jiao. In 2011, he joined the group of Prof. Frank Glorius at Westfalische Wilhelms-Universitat Münster, as an Alexander von Humboldt Research Fellow studying Rh(III)-catalyzed C–H activation reactions. Since March 2014, he is working as a full professor at the Nanjing University, focusing on the development of new transition-metal catalysts and synthetic methodology.

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Introduction

Compared with traditional coupling reactions, the direct functionalization of C–H bonds exhibits more advantages due to its atom and step economy, especially when the introduction of halides in a specific synthesis intermediate is difficult.¹ In particular, transition metal catalysis has emerged as a powerful tool for the functionalization of otherwise unreactive sp² C–H in the past decades.² The aliphatic C–H bonds, which are ubiquitous in organic molecules are the most challenging targets for effective and selective functionalization.³ Among them, notable advances have been made in the direct C–H arylation reactions through a variety of developed strategies. Initial studies focused on the direct arylation of 8-methylquinoline due to its good chelating abilities.⁴ Later on, external ligands were added to facilitate the Pd-catalyzed direct arylation of aliphatic acids, amides, amino acid derivatives and peptides.⁵ In addition, the utilization of bidentate chelating groups such as 8-aminoquinoline and picolinamide was also a powerful strategy to promote the C–H arylations.⁶ Despite the great progress made in this field, the current substrates are still limited to aliphatic acids, amides and the related compounds. Therefore, new catalytic systems need to be developed to expand the scope to other types of compounds.

Oxime ethers as the precursor of ketones, amines, amides and cyanos are among the most useful functional building blocks available to the synthetic chemists. The β-oxygenation⁷ and amination⁸ of aliphatic C–H bonds in ketoxime derivatives have been exploited. Considering the wide existence of β-arylated ketones in natural products and pharmaceuticals,⁹ it is well worth developing a method to introduce a phenyl group in the β-position of oxime ethers via aliphatic C–H activation. In 2015, our group first developed a versatile method for the direct arylation of sp³ C–H bonds in O-methyl ketoximes and nitrogen-containing heterocycles.¹⁰ The key to this success depends on the appropriate choice of an Ir(III) catalyst and the use of diaryliodonium triflate salts as the coupling partners (Scheme 1a, Ir catalysis). Very recently, Chen and co-workers uncovered that the same transformation can occur in the presence of Pd catalysts (Scheme 1a, Pd catalysis).¹¹ In view of the diaryliodonium salts, as costly and less available reagents with a low atom economy, we are encouraged to discover a milder catalytic system using a more accessible phenyl source. Herein, we report the Pd-catalyzed intermolecular direct arylation of the sp³ C–H bonds in O-methyl ketoximes with iodoarenes (Scheme 1b). Our latest method demonstrates a perfect adaptability of a wide range of substrates and proceeds smoothly in late-stage C–H functionalization, which provides a meaningful perspective in future research.

Scheme 1 Iridium- and palladium-catalyzed direct C–H arylation of O-methyl ketoximes.

Results and discussion

We started our research on the Pd-catalyzed C–H arylation of the readily available 2,3-dimethylcyclohex-2-en-1-one oxime (1a) and iodobenzene (2a) for the optimization of reaction conditions (Table 1). Initial studies focused on the sources of silver oxidants (entries 1–3). It was found that AgTFA was very critical to the reaction and provided the desired product 3aa in 31% yield at 100 °C using DCE as the solvent. The effects of various solvents were also examined and PhCF₃ demonstrated the best effects (entry 4). Notably, lowering the temperature to 80 °C led to an improvement in the reaction outcome (entries 5 and 6). We also screened several different kinds of ligands from L1 to L7, and found that only organic phosphate L5–L6 can give positive effects (entries 7 and 8).¹² Simple phosphate BINPO₂H, commercially available at low cost, was the most effective affording 3aa in 80% yield. Under these conditions, reducing the amount of AgTFA or Pd(OAc)₂ led to lower yields (entries 9 and 10). In addition, other palladium sources including Pd(TFA)₂ and Pd₂(dba)₃ showed comparatively poor yields and obviously, the absence of a catalyst failed to provide the corresponding product (Table 1, entries 11–13). Based on the above results, it was revealed that entry 8 illustrated the optimal conditions for the Pd-catalyzed arylation of O-methyl ketoxime 1a.

Table 1 Optimization of the reaction conditions^a

Entry	[Pd] (mol%)	L	Oxidant (equiv.)	Solvent	T	Yield^b (%)
a Reaction conditions: all the reactions were run on the 0.20 mmol scale with 1a (1.0 equiv.), 2a (2.0 equiv.), palladium catalyst (5 mol%), ligand (10 mol%) and silver oxidant (2.0 equiv.) in 1.0 mL solvent, 12 h. b Crude ^1H NMR yield using CH2Br2 as the internal standard. c Isolated yield in parentheses.
1	Pd(OAc)2 (5)	—	Ag2CO3 (2.0)	DCE	100	Trace
2	Pd(OAc)2 (5)	—	AgOAc (2.0)	DCE	100	5
3	Pd(OAc)2 (5)	—	AgTFA (2.0)	DCE	100	31
4	Pd(OAc)2 (5)	—	AgTFA (2.0)	PhCF3	100	42
5	Pd(OAc)2 (5)	—	AgTFA (2.0)	PhCF3	80	65
6	Pd(OAc)2 (5)	—	AgTFA (2.0)	PhCF3	60	54
7	Pd(OAc)2 (5)	L1	AgTFA (2.0)	PhCF3	80	37
8	Pd(OAc) 2 (5)	L6	AgTFA (2.0)	PhCF 3	80	80 (73)
9	Pd(OAc)2 (5)	L6	AgTFA (1.0)	PhCF3	80	47
10	Pd(OAc)2 (2.5)	L6	AgTFA (2.0)	PhCF3	80	56
11	Pd(TFA)2 (5)	L6	AgTFA (2.0)	PhCF3	80	63
12	Pd(dba)2 (5)	L6	AgTFA (2.0)	PhCF3	80	53
13	—	L6	AgTFA (2.0)	PhCF3	80	0

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With the best conditions in hand, we sought to expand this transformation to the transfer of diverse aryl groups and we found that a range of substituted iodoarenes worked well with 2,3-dimethylcyclohex-2-en-1-one oxime (1a) (Table 2). Aromatic groups displaying electron-neutral and electron-rich substituents at the meta- and para-positions (3ab–3ad & 3ae–3ag) were transferred in particularly good yields from the corresponding iodoarenes. Useful halogenated iodoarenes such as trifluoromethyl-(3ah–3ai), fluoro-(3aj), chloro-(3ak) and even bromo-(3al) groups were accommodated, thereby providing possibilities for subsequent chemical transformations. Electron-withdrawing substituted groups such as acetyl- (3am) and methyl ester (3an) groups could be tolerated in this protocol. We were pleased that the coupling of the polycyclic aromatic motif was possible and proceeded in moderate yield (3ao), thus further enhancing the scope of our reaction.

Table 2 Substrate scope of iodoarenes 2^a

a Reaction conditions: all the reactions were run on the 0.20 mmol scale with 1a (1.0 equiv.), 2 (2.0 equiv.), Pd(OAc)₂ (5 mol%), L6 (10 mol%) and AgTFA (2.0 equiv.) in 1.0 mL PhCF₃, 12 h; isolated yields.

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When 2-iodobenzoic acid (2p) was employed as an ortho-substituted substrate, an unexpected five-membered lactone 3ap was observed in 62% yield under the optimized conditions (Scheme 2). Other substrates involving methyl-, chloro- and bromo-groups were well-tolerated, and the corresponding products 3aq–3as were isolated in 50%–63% yields. In addition, 2-iodo-4,5-dimethoxybenzoic acid (2t) was also compatible affording the cyclization product 3at in 54% yield. We speculated that the β-C–H arylation of O-methyl ketoximes with 2-iodobenzoic acids could afford the C–H arylation products as shown in Table 2, which caused further intramolecular C–H oxygenation in the presence of ortho-carboxylic acid groups. Although the cyclization reactions via multiple palladium-catalyzed C–H activation of arenes have been developed,¹³ this tandem sp³ C–H arylation and oxygenation process has seldom been reported.

Scheme 2 Cyclization of 2-iodobenzoic acids 2p–2t by dual C–H activation.

We next investigated the substrate scope of O-methyl ketoximes with iodobenzene (2a) in Table 3. β-Arylation of ketoxime 1b, which contains a quaternary α-carbon atom, gave the monoarylated product 3ba in 77% yield. In the case of substrates 1c–1d, with the increasing of steric bulk from n-heptyl to cyclohexyl adjacent to the quaternary centers, the yield of the corresponding products gradually decreased. It should be mentioned that these substrates contain multiple possible sites for the direct arylation, showing extremely high selectivity for activation of primary β-C–H bonds in lieu of those at secondary carbon centers. Later on, we tested the substrates with several primary β-C–H bonds that can be functionalized. Gratifyingly, we were able to functionalize pinacolone derivative 1e and 1f to give a mixture of mono- and diarylated products in 73% and 77% yield, respectively. It's also noticed that the methyl groups adjacent to a quaternary center is necessary for this C–H arylation and oxime ethers with α-hydrogens having much lower reactivity, since O-methyl ketoxime 3ga only gave trace amounts of the product.

Table 3 Substrate scope of O-methyl ketoximes 1^a

a Reaction conditions: all the reactions were run on the 0.20 mmol scale with 1 (1.0 equiv.), 2a (2.0 equiv.), Pd(OAc)₂ (5 mol%), L6 (10 mol%) and AgTFA (2.0 equiv.) in 1.0 mL PhCF₃, 12 h; isolated yields.

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Late-stage modification of naturally significant molecules to access new bioactive compounds have been an emerging concept in organic chemistry.¹⁴ Encouraged by this successful sp³ C–H arylation, we also turned our attention to utilize our method as a key step for the regioselective C–H arylation of a complex molecule. O-Methyl ketoxime 5, derived from pharmaceutical compound Santonin 4, a kind of roundworm repellent, was compatible to this catalytic system affording the desired product 6 in 61% yield. The structure of 6 was further confirmed by X-ray diffraction as shown in Scheme 3.

Scheme 3 Late-stage C–H arylation of santonin.

Chen and co-workers previously uncovered that Pd-catalyzed C–H arylation of O-methyl ketoximes with diaryliodonium salt triggered by the palladium species inducing C–H activation of the O-methyl ketoxime to generate a palladacycle complex.^11,15 However, when the complex le′ was synthesized and treated with 2.0 equiv. of 2a and 2.0 equiv. of AgTFA, we didn't observe any corresponding arylated products (Scheme 4). We hypothesized that oxidative addition of the palladium species to iodoarenes should take place ahead of the C–H activation of O-methyl ketoximes under our conditions.

Scheme 4 Mechanistic investigations.

Conclusions

In summary, we have developed examples of the palladium-catalyzed C–H arylation of O-methyl ketoximes with iodoarenes under mild conditions. This novel method exhibited flexibility with different substrates and offered new opportunities to prepare β-arylated O-methyl ketoximes from inexpensive and available reagents. The efficient strategy not only tolerated various functional groups, but has also been applied to the modification of complex molecules. Also, a series of five-membered lactones could be generated from 2-iodobenzoic acids under standard conditions. Further studies on the mechanism and applications of this novel method are going to be researched by our group.

Acknowledgements

We thank the “1000-Youth Talents Plan”, the “Jiangsu Specially-Appointed Professor Plan”, NSF of China (Grant 21402086), and NSF of Jiangsu Province (Grant BK20140594) for financial support. This work was also supported by a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Notes and references

1. (a) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (b) B. Li, S. Yang and Z. Shi, Synlett, 2008, 949; (c) K. Godula and D. Sames, Science, 2006, 312, 67; (d) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (e) L. Ackermann, R. Vincente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; (f) O. Dougulis, H.-Q. Do and D. Shabashov, Acc. Chem. Res., 2009, 42, 1074; (g) G. P. McGlacken and L. M. Bateman, Chem. Soc. Rev., 2009, 38, 2447; (h) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (i) O. Baudoin, Chem. Soc. Rev., 2011, 40, 4902; (j) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960; (k) P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012, 112, 5879; (l) G. Rouquet and N. Chatani, Angew. Chem., Int. Ed., 2013, 52, 11726.
2. Recent reviews on the transition-metal-catalyzed C–H activation reactions: (a) M. Lautens and P. Thansandote, Chem. – Eur. J., 2009, 15, 5874; (b) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel and J.-Q. Yu, Chem. Soc. Rev., 2009, 38, 3242; (c) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer and O. Baudoin, Chem. – Eur. J., 2010, 16, 2654; (d) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (e) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068; (f) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111, 1293; (g) J. Wencel-Delord, T. Dröge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; (h) T. Newhouse and P. S. Baran, Angew. Chem., Int. Ed., 2011, 50, 3362; (i) L. Ackermann, Chem. Rev., 2011, 111, 1315; (j) L. McMurray, F. O'Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885; (k) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (l) Z. Shi, C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3381; (m) B.-J. Li and Z.-J. Shi, Chem. Soc. Rev., 2012, 41, 5588; (n) M. C. White, Science, 2012, 335, 807; (o) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45, 788; (p) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960; (q) S. R. Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012, 45, 936; (r) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord and F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 10236; (s) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369; (t) X.-X. Cuo, D.-W. Gu, Z. Wu and W. Zhang, Chem. Rev., 2015, 115, 1622.
3. Recent reviews on the transition-metal-catalyzed sp³ C–H activation reactions: (a) G. Chen and Z.-J. Shi, Natl. Sci. Rev., 2014, 1, 272; (b) G. Qiu and J. Wu, Org. Chem. Front., 2015, 2, 169; (c) S.-Y. Zhang, F.-M. Zhang and Y.-Q. Tu, Chem. Soc. Rev., 2011, 40, 1937.
4. (a) D. Kalyani, N. R. Deprez, L. V. Desai and M. S. Sanford, J. Am. Chem. Soc., 2005, 127, 7330; (b) O. Daugulis and D. Shabashov, Org. Lett., 2005, 7, 3657; (c) K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2007, 129, 11904; (d) W.-Y. Yu, W. Sit, Z. Zhou and A. S.-C. Chan, Org. Lett., 2009, 11, 3174; (e) M. Kim, J. Kwak and S. Chang, Angew. Chem., Int. Ed., 2009, 48, 8935.
5. (a) R. Giri, Y. Lan, P. Liu, K. N. Houk and J.-Q. Yu, J. Am. Chem. Soc., 2012, 134, 14118; (b) K. S. L. Chan, M. Wasa, L. Chu, B. N. Laforteza, M. Miura and J.-Q. Yu, Nat. Chem., 2014, 6, 146; (c) J. He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A. Homs and J.-Q. Yu, Science, 2014, 343, 1216; (d) K.-J. Xiao, D. W. Lin, M. Miura, R.-Y. Zhu, W. Gong, M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2014, 136, 8138; (e) Q. Deng, W. Gong, J. He and J.-Q. Yu, Angew. Chem., Int. Ed., 2014, 53, 6692.
6. (a) V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am. Chem. Soc., 2005, 127, 13154; (b) G. He and G. Chen, Angew. Chem., Int. Ed., 2011, 50, 5192; (c) Q. Zhang, K. Chen, W.-H. Rao, Y. Zhang, F.-J. Chen and B.-F. Shi, Angew. Chem., Int. Ed., 2013, 52, 13588; (d) F. Pan, P.-X. Shen, L.-S. Zhang, X. Wang and Z.-J. Shi, Org. Lett., 2013, 15, 4758; (e) R. Shang, L. Ilies, A. Matsumoto and E. Nakamura, J. Am. Chem. Soc., 2013, 135, 6030; (f) K. Chen and B.-F. Shi, Angew. Chem., Int. Ed., 2014, 53, 11950; (g) Y. Aihara and N. Chatani, J. Am. Chem. Soc., 2014, 136, 898; (h) Q. Gu, H. H. A. Mamari, K. Graczyk, E. Diers and L. Ackermann, Angew. Chem., Int. Ed., 2014, 53, 3868.
7. (a) L. V. Desai, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2004, 126, 9542; (b) Z. Ren, F. Mo and G. Dong, J. Am. Chem. Soc., 2012, 134, 16991; (c) Y. Xu, G. Yan, Z. Ren and G. Dong, Nat. Chem., 2015, 7, 829; (d) S. J. Thompson, D. Q. Thach and G. Dong, J. Am. Chem. Soc., 2015, 137, 11586.
8. (a) H. Wang, G. Tang and X. Li, Angew. Chem., Int. Ed., 2015, 54, 13049; (b) T. Kang, Y. Kim, D. Lee, Z. Wang and S. Chang, J. Am. Chem. Soc., 2014, 136, 4141; (c) T. Kang, H. Kim, J. G. Kim and S. Chang, Chem. Commun., 2014, 50, 12073; (d) H.-Y. Thu, W.-Y. Yu and C.-M. Che, J. Am. Chem. Soc., 2006, 128, 9048.
9. (a) U. Ryuji, U.S. Pat. Appl. Publ, US 20010034355, 2001; (b) S. Wang, C. Zhang, G. Yang and Y. Yang, Nat. Prod. Commun., 2014, 9, 1027; (c) J. S. Choi, H. J. Park, H. A. Jung, H. Y. Chung, J. H. Jung and W. C. Choi, J. Nat. Prod., 2000, 63, 1705; (d) K. Amagase, Y. Kimura, A. Wada, T. Yukishige, T. Murakami, E. Nakamura and K. Takeuchi, Curr. Pharm. Des., 2014, 20, 2783.
10. P. Gao, W. Guo, J. Xue, Y. Zhao, Y. Yuan, Y. Xia and Z. Shi, J. Am. Chem. Soc., 2015, 137, 12231.
11. J. Peng, C. Chen and C. Xi, Chem. Sci., 2015 10.1039/c5sc03903g.
12. (a) S.-Y. Zhang, Q. Li, G. He, W. A. Nack and G. Chen, J. Am. Chem. Soc., 2013, 135, 12135; (b) S.-Y. Zhang, G. He, W. A. Nack, Y. Zhao, Q. Li and G. Chen, J. Am. Chem. Soc., 2013, 135, 2124.
13. (a) V. S. Thirunavukkarasu, K. Parthasarathy and C.-H. Cheng, Angew. Chem., Int. Ed., 2008, 47, 9462; (b) J. Karthikeyan and C.-H. Cheng, Angew. Chem., Int. Ed., 2011, 50, 9880; (c) P. Gandeepan, K. Parthasarathy and C.-H. Cheng, J. Am. Chem. Soc., 2010, 132, 8569.
14. (a) W. R. Gutekunst, R. Gianatassio and P. S. Baran, Angew. Chem., Int. Ed., 2012, 51, 7507; (b) H. M. Davies and J. R. Manning, Nature, 2008, 451, 417; (c) W. R. Gutekunst and P. S. Baran, J. Am. Chem. Soc., 2011, 133, 19076; (d) L. McMurray, F. Ohara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885; (e) E. M. Simmons and J. F. Hartwig, Nature, 2012, 483, 70; (f) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369.
15. A. McNally, B. Haffemayer, B. S. L. Collins and M. Gaunt, Nature, 2014, 510, 129.

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1444168. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00438a

‡ These authors contributed equally to this work.

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