meta-C–H functionalization of phenylethyl and benzylic alcohol derivatives via Pd/NBE relay catalysis

Abstract

The transition metal-catalyzed meta-C–H functionalization of alcohols and their hydroxylamine derivatives remains underdeveloped. Herein, we report an efficient meta-C–H arylation of both phenylethyl and benzylic alcohols and their hydroxylamine derivatives using a readily removable oxime ether directing group. Using electronically activated 2-carbomethoxynorbornene as the transient mediator and 3-trifluoromethyl-2-pyridone as the enabling ligand, this reaction features a broad substrate scope and good functional group tolerance. More importantly, with this oxime-directed meta-C–H functionalization, this method provides a dual approach for efficient access to both meta-substituted alcohols and hydroxylamines using two sets of simple deprotection conditions. This protocol leads to the efficient synthesis of bioactive compounds possessing promising reactivities for the treatment of pulmonary fibrosis.

---

Introduction

Phenylethyl and benzylic alcohols and their hydroxylamine derivatives are commonly found in a wide range of bioactive molecules, including tolvaptan, prothioconazole, tramadol, fenaminstrobin, siponimod etc. (Scheme 1a).¹ In addition, they are also significant and widely utilizable synthetic building blocks that can engage in many fundamental transformations² and heterocycle constructions.³ Thus, developing general and practical C–H transformations of alcohols and their hydroxylamine derivatives are highly valuable for late-stage diversification of alcohol or hydroxylamine containing bioactive scaffolds. Although transition metal catalyzed ortho-C–H functionalization of aryl alcohols has been well studied,⁴ diverse meta-C–H functionalizations of those substrates are relatively less common and inefficient in both substrate and coupling partner scope^5,6 in spite of significant progress in the field of transition metal catalyzed meta-C–H activation.^7–10 Taking advantage of the Pd/NBE relay approach^6,9 for efficient meta-C–H functionalization, the only example of meta-arylation of benzylic alcohol derivatives has been reported by the Ferreira group (Scheme 1b). However, this reaction is limited to benzylic alcohols and a large excess of aryl iodides (4.0 equiv.) is required to give synthetically useful yields.⁶ Furthermore, the preparation of the directing group in this reaction is not straightforward. Herein, we report a palladium-catalyzed meta-C–H functionalization of oxime ethers using 2-carbomethoxynorbornene (NBE-CO₂Me) as a transient mediator and commercially available 3-trifluoromethyl-2-pyridone as the ligand (Scheme 1d). This reaction features a broad substrate scope and good functional group tolerance. More importantly, with this oxime-directed meta-C–H functionalization, this method provides a “one stone two birds” approach (Scheme 1c) for efficient access to meta-substituted alcohols and hydroxylamines by the removal of the directing group under different conditions.

Scheme 1 meta-C–H functionalization of alcohol and hydroxylamine via Pd/NBE relay catalysis.

Results and discussion

Our group has reported palladium-catalyzed hydroxy-directed ortho-C–H olefination of tertiary phenethyl alcohols with the assistance of an MPAA ligand.^4a–c However, directed meta-C–H arylation using the native hydroxy group under our previous meta-C–H arylation conditions resulted in no reaction and the slight decomposition of the primary alcohol. Despite methyl ether (DG²) being stable under these conditions, no desired product was observed either. Although the pyridine directing group DG³ is inert, we are pleased to find that the acetone oxime directing group (DG⁴) could provide the desired meta-arylated product in 14% NMR yield. Cyclohexanone oxime ether (DG⁵) also showed similar reactivity (Table 1). Following this finding, systematic evaluation of reaction parameters was conducted to further improve the outcomes using the acetone oxime ether as the directing group (Table 2). Notably, fluorinated alcohols can raise the yield drastically, and 2,2-difluoroethanol was identified as the most efficient solvent for this reaction due to the better mass balance (for more details, see the ESI†). With 2,2-difluoroethanol as the optimal solvent, the ligand effect was further evaluated, and we are pleased to find that the pyridone ligands are superior to the mono-protected amino acid (MPAA) ligand (L1), pyridine ligand (L2), and bulky carboxylic acid (L3). In general, both electron-rich (L4, L5) and electron-deficient (L6–8) 2-pyridone ligands could dramatically improve the yield of this reaction, in which commercially available 3-trifluoromethyl-2-pyridone L8 gave the best outcome (87% yield). Switching the CF₃ group to other positions at the 2-pyridone scaffold (L9, L10) or more electron-deficient 2-pyridone ligands (L11, L12) cannot further enhance the reactivity. The mono-protected 3-amino-2-pyridone ligands (L13, L14) also provide the desired product in 68% and 85% yields, respectively. It is worth mentioning that the control experiments indicate the pyridone ligand is crucial for accelerating this meta-arylation of phenethyl alcohol-derived oxime ether, and only 21% NMR yield of the desired product was obtained in the absence of ligand.

Table 1 Directing group evaluation for meta-C–H functionalization of alcohol derivatives^ab

a Reaction conditions: substrate (0.1 mmol), 2j (52.4 mg, 0.2 mmol), Pd(OAc)₂ (2.2 mg, 10 mol%), L14 (4.4 mg, 20 mol%), AgOAc (25.0 mg, 0.15 mmol), NBE-CO₂Me (22.8 mg, 0.15 mmol), CHCl₃ (0.5 mL), air, 100 °C, 12 h. b The yield was determined by ¹H NMR analysis of the crude product using CH₂Br₂ as the internal standard.

---

Table 2 Ligand evaluation for Pd-catalyzed meta-C–H functionalization of oxime ethers^ab

a Reaction conditions: 1 (19.1 mg, 0.1 mmol), 2j (52.4 mg, 0.2 mmol), Pd(OAc)₂ (2.2 mg, 10 mol%), L (20 mol%), AgOAc (25.0 mg, 0.15 mmol), NBE-CO₂Me (22.8 mg, 0.15 mmol), CF₂HCH₂OH (0.1 mL), air, 100 °C, 12 h. b The yield was determined by ¹H NMR analysis of the crude product using CH₂Br₂ as the internal standard.

---

Under the optimal conditions, the scope of aryl iodides was evaluated using 2-(m-tolyl)ethan-1-ol derived acetone oxime 1 as the model substrate (Table 3). In general, para-substituted aryl iodides containing both electron-rich substituents (2b–d) and electron-deficient substituents (2e–l) were all suitable coupling partners, providing the desired meta-arylated products in 40–84% yields. The 3-substituted (2m, 2n) aryl iodides showed similar reactivities in comparison to the para-substituted aryl iodides. Under the highly acidic conditions, 2-substituted aryl iodides are highly active, resulting in more side products via the classic Catellani reaction pathway. Accordingly, less reactive aryl bromides (2o, 2p) provide higher yields than the corresponding aryl iodides. Multiple substituted aryl iodides (3q–t) were also evaluated, affording the desired products in good yields. Notably, the heteroaryl iodides, containing pyridine (2u, 2v) and thiophene (2w) motifs, were well tolerated with this procedure. Aryl iodides derived from estrone (2x) and ciprofibrate (2y) were also investigated, which further demonstrated the generality of this reaction towards the complex scaffold.

Table 3 Scope of aryl iodides^abc

a Reaction conditions: 1 (38.3 mg, 0.2 mmol), 2 (0.4 mmol), Pd(OAc)₂ (4.5 mg, 10 mol%), L8 (6.5 mg, 20 mol%), AgOAc (50.1 mg, 0.30 mmol), NBE-CO₂Me (45.7 mg, 0.30 mmol), CF₂HCH₂OH (0.2 mL), 100 °C, 12 h. b Isolated yield. c Ar–Br was used instead of Ar–I.

---

Next, we turned our attention to check the breadth of aromatic oxime substrates (Table 4). The simple phenethyl alcohol-derived acetone oxime ether (4a) gave a mixture of mono- and di-products in 69% total yield with a mono/di ratio of 1.5/1.0. The phenethyl alcohol-derived oxime ethers bearing both electron-donating and electron-withdrawing substituents at the 3-position (4b–h), such as phenyl, methoxy, trifluoromethoxy, and acetylamino groups and halides, were all tolerated, providing the desired products in high efficiency. For ortho-substituted phenethyl alcohol derivatives (4i–l), 2,2,2-trifluoroethanol (TFE) was found to be a more efficient solvent than CF₂HCH₂OH, giving the arylated products in 43–76% yields. The meta-C–H bond on the thiophene ring could also be arylated (4m) with a lower yield probably due to the stability of the substrate under the reaction conditions.

Table 4 Scope of acetone oxime ethers^abcde

a Reaction conditions: 4 (0.2 mmol), 2j (104.8 mg, 0.4 mmol), Pd(OAc)₂ (4.5 mg, 10 mol%), L8 (6.5 mg, 20 mol%), AgOAc (50.1 mg, 0.30 mmol), NBE-CO₂Me (45.7 mg, 0.30 mmol), CF₂HCH₂OH (0.2 mL), 100 °C, 12 h. b Isolated yield. c TFE was used. d AgOAc (100.1 mg, 0.60 mmol) was used. e L14 was used instead of L8.

---

To our delight, phenethyl alcohols bearing both α- (4n–o) and β-substituents (4p–r) were tolerated with this procedure (4n–s), indicating the great potential of the current method for late-stage modification of complex primary and secondary alcohols. Less challenging benzylic alcohol derivatives with various substituents on the aromatic ring (4t–v) and the benzyl position (4w–y) were also investigated. Generally, the benzylic alcohol derived substrates showed higher reactivities than phenethyl alcohols.

The scalability of this reaction was demonstrated by conducting this reaction on a 5.0 mmol scale, affording the desired arylated product 3j in 86% yield (Scheme 2a). Gratifyingly, the acetone oxime directing group could be selectively converted to alcohol 7 and hydroxylamine 6 in high yields under reductive conditions and mild hydrolysis conditions, respectively. The newly developed protocol could not only provide an efficient strategy for the late-stage installation of functionalities at the meta-position of the aromatic alcohols and their hydroxylamine derivatives, but also paved a new way for the synthesis of bioactive compounds. For example, the 2,5-diaryl substituted phenylethanol 11 and its hydroxylamine derivative 12, both possessing promising reactivities for the treatment of pulmonary fibrosis,¹¹ could be prepared in high efficiency within three steps by leveraging our method as the key synthetic step (Scheme 2c). For comparison, those compounds were prepared in nine (for 11) or eleven steps (for 12) starting from 5-bromo-2-hydroxybenzaldehyde.¹¹

Scheme 2 Gram-scale reaction and synthetic applications.

Based on the previous works on the meta-C–H activation via Pd/NBE relay catalysis,⁹ a proposed mechanism is depicted in Scheme 3. Firstly, oxime directed ortho-C–H activation occurs to give Int I, followed by the migration insertion of NBE-CO₂Me, and sequential meta-C–H activation to generate Int II. The meta-functionalization happened via the oxidative addition with aryl iodide and reductive elimination. NBE-CO₂Me could be regenerated by β-C elimination, and the product was formed via protodemetalation of Int IV.

Scheme 3 Proposed mechanism.

Conclusions

In summary, a Pd-catalyzed meta-functionalization of oxime ethers was realized by using Pd/NBE relay catalysis. The 3-trifluoromethyl pyridone ligand was identified as the enabling ligand, which could significantly enhance the efficiency of this meta-functionalization. This procedure features a broad substrate scope and remarkable functional group compatibility, thus paving a practical way for the construction of meta-substituted alcohols and their hydroxylamine derivatives.

Data availability

The data supporting this article have been included as part of the ESI.†

Author contributions

H.-C. S. and J.-J. L. performed the experiments and analysed the data. P. W. guided the experiments. P. W. and J.-Q. Y. conceived this concept and prepared this manuscript with feedback from H.-C. S. and J.-J. L.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the National Key R&D Program of China (2023YFF0723900), National Natural Science Foundation of China (22371293, 22171277, 22101291), Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0610000), Program of Shanghai Academic/Technology Research Leader (23XD1424500), Shanghai Institute of Organic Chemistry (SIOC), and State Key Laboratory of Organometallic Chemistry for financial support. We also thank J.-P. Wang at SIOC for verifying the reproducibility of this work.

Notes and references

1. (a) R. W. Schrier, P. Gross, M. Gheorghiade, T. Berl, J. G. Verbalis, F. S. Czerwiec and C. Orlandi, N. Engl. J. Med., 2006, 355, 2099–2112; (b) J. E. Parker, A. G. Warrilow, H. J. Cools, C. M. Martel, W. D. Nes, B. A. Fraaije, J. A. Lucas, D. E. Kelly and S. L. Kelly, Appl. Environ. Microbiol., 2011, 77, 1460–1465; (c) W. Richter, H. Barth, L. Flohe and H. Giertz, Arzneimittelforschung, 1985, 35, 1742–1744; (d) M. Ishaque, G. Schnabel and D. D. Anspaugh, WO2009/153231A2, 2009; (e) P. Gergely, B. Nuesslein-Hildesheim, D. Guerini, V. Brinkmann, M. Traebert, C. Bruns, S. Pan, N. Gray, K. Hinterding, N. Cooke, A. Groenewegen, A. Vitaliti, T. Sing, O. Luttringer, J. Yang, A. Gardin, N. Wang, W. Crumb, M. Saltzman, M. Rosenberg and E. Wallström, Br. J. Pharmacol., 2012, 167, 1035–1047.
2. R. C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Wiley-VCH, New York, 2nd edn, 1989.
3. For selected examples, see: (a) T. Kondo, S. Yang, K.-T. Huh, M. Kobayashi, S. Kotachi and Y. Watanabe, Chem. Lett., 1991, 20, 1275–1278; (b) J. Zhou and J. Fang, J. Org. Chem., 2011, 76, 7730–7736; (c) H.-J. Li, C.-C. Wang, S. Zhu, C.-Y. Dai and Y.-C. Wu, Adv. Synth. Catal., 2015, 357, 583–588.
4. For free hydroxyl group directed ortho-C–H activation, see: (a) Y. Lu, D.-H. Wang, K. M. Engle and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 5916–5921; (b) X. Wang, Y. Lu, H.-X. Dai and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 12203–12205; (c) Y. Lu, D. Leow, X. Wang, K. M. Engle and J.-Q. Yu, Chem. Sci., 2011, 2, 967–971; (d) K. Morimoto, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2011, 76, 9548–9551; (e) L. Li, Q. Liu, J. Chen and Y. Huang, Synlett, 2019, 30, 1366–1370; (f) D. A. Strassfeld, C.-Y. Chen, H. S. Park, D. Q. Phan and J.-Q. Yu, Nature, 2023, 622, 80–86 ; For selected examples of ortho-C–H activation with a directing group, see: ; (g) E. M. Simmons and J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 17092–17095; (h) K. Guo, X. Chen, M. Guan and Y. Zhao, Org. Lett., 2015, 17, 1802–1805; (i) Z. Ren, J. E. Schulz and G. Dong, Org. Lett., 2015, 17, 2696–2699; (j) L.-Y. Shao, C. Li, Y. Guo, K.-K. Yu, F.-Y. Zhao, W.-L. Qiao, H.-W. Liu, D.-H. Liao and Y.-F. Ji, RSC Adv., 2016, 6, 78875–78880; (k) B. J. Knight, J. O. Rothbaum and E. M. Ferreira, Chem. Sci., 2016, 7, 1982–1987; (l) Y.-J. Mao, S.-J. Lou, H.-Y. Hao and D.-Q. Xu, Angew. Chem., Int. Ed., 2018, 57, 14085–14089.
5. (a) D. S. Leow, G. Li, T.-S. Mei and J.-Q. Yu, Nature, 2012, 486, 518–522; (b) S. Lee, H. Lee and K. L. Tan, J. Am. Chem. Soc., 2013, 135, 18778–18781; (c) L. Chu, M. Shang, K. Tanaka, Q. H. Chen, N. Pissarnitski, E. Streckfuss and J.-Q. Yu, ACS Cent. Sci., 2015, 1, 394–399; (d) L. Zhang, C. Zhao, Y. Liu, J. Xu, X. Xu and Z. Jin, Angew. Chem., Int. Ed., 2017, 56, 12245–12249; (e) S.-D. Li, H. Wang, Y.-X. Weng and G. Li, Angew. Chem., Int. Ed., 2019, 58, 18502–18507; (f) H. Xu, M. Liu, L.-J. Li, Y.-F. Cao, J.-Q. Yu and H.-X. Dai, Org. Lett., 2019, 21, 4887–4891.
6. Q. Li and E. M. Ferreira, Chem.–Eur. J., 2017, 23, 11519–11523.
7. For a review on template-directed meta-C–H functionalization, see: (a) G. Meng, N. Y. S. Lam, E. L. Lucas, T. G. Saint-Denis, P. Verma, N. Chekshin and J.-Q. Yu, J. Am. Chem. Soc., 2020, 142, 10571–10591 . For selected examples, see: ; (b) L. Wan, N. Dastbaravardeh, G. Li and J.-Q. Yu, J. Am. Chem. Soc., 2013, 135, 18056–18059; (c) R. Tang, G. Li and J.-Q. Yu, Nature, 2014, 507, 215–220; (d) Y. Kuninobu, H. Ida, M. Nishi and M. Kanai, Nat. Chem., 2015, 7, 712–717; (e) H. J. Davis, M. T. Mihai and R. J. Phipps, J. Am. Chem. Soc., 2016, 138, 12759–12762; (f) Z. Zhang, K. Tanaka and J.-Q. Yu, Nature, 2017, 543, 538–542.
8. For a review on ruthenium(II)-catalyzed meta-C–H functionalization by ortho-cyclometallation, see: (a) J. A. Leitch and C. G. Frost, Chem. Soc. Rev., 2017, 46, 7145–7153 ; for selected examples, see:; (b) O. Saidi, J. Marafie, A. E. W. Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Kçhn, M. K. Whittlesey and C. G. Frost, J. Am. Chem. Soc., 2011, 133, 19298–19301; (c) N. Hofmann and L. Ackermann, J. Am. Chem. Soc., 2013, 135, 5877–5884; (d) C. J. Teskey, A. Y. W. Lui and M. F. Greaney, Angew. Chem., Int. Ed., 2015, 54, 11677–11680; (e) Z. Fan, J. Ni and A. Zhang, J. Am. Chem. Soc., 2016, 138, 8470–8475; (f) C. C. Yuan, X. L. Chen, J. Y. Zhang and Y. S. Zhao, Org. Chem. Front., 2017, 4, 1867–1871; (g) Y. Wang, S. Chen, X. Chen, A. Zangarelli and L. Ackermann, Angew. Chem., Int. Ed., 2022, 61, e202205562; (h) J. Wu, N. Kaplaneris, J. Pöhlmann, T. Michiyuki, B. Yuan and L. Ackermann, Angew. Chem., Int. Ed., 2022, 61, e202208620.
9. For selected examples on meta-C–H arylation using a palladium/norbornene relay process, see: (a) X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu, S. Li, K. M. Engle and J.-Q. Yu, Nature, 2015, 519, 334–338; (b) Z. Dong, J. Wang and G. Dong, J. Am. Chem. Soc., 2015, 137, 5887–5890; (c) P.-X. Shen, X.-C. Wang, P. Wang, R.-Y. Zhu and J.-Q. Yu, J. Am. Chem. Soc., 2015, 137, 11574–11577; (d) P. Wang, M. E. Farmer, X. Huo, P. Jain, P.-X. Shen, M. Ishoey, J. E. Bradner, S. R. Wisniewski, M. D. Eastgate and J.-Q. Yu, J. Am. Chem. Soc., 2016, 138, 9269–9276; (e) P. Wang, G.-C. Li, P. Jain, M. E. Farmer, J. He, P.-X. Shen and J.-Q. Yu, J. Am. Chem. Soc., 2016, 138, 14092–14099; (f) H. Shi, P. Wang, S. Suzuki, M. E. Farmer and J.-Q. Yu, J. Am. Chem. Soc., 2016, 138, 14876–14879; (g) J. Han, L. Zhang, Y. Zhu, Y. Zheng, X. Chen, Z.-B. Huang, D.-Q. Shi and Y. Zhao, Chem. Commun., 2016, 52, 6903–6906; (h) H. Shi, A. N. Herron, Y. Shao, Q. Shao and J.-Q. Yu, Nature, 2018, 558, 581–585; (i) L.-Y. Liu, J. X. Qiao, K.-S. Yeung, W. R. Ewing and J.-Q. Yu, J. Am. Chem. Soc., 2019, 141, 14870–14877; (j) R. Li, Y. Zhou, X. Xu and G. Dong, J. Am. Chem. Soc., 2019, 141, 18958–18963; (k) V. Sukowski, M. van Borselen, S. Mathew and M. Á. Fernández-Ibáñe, Angew. Chem., Int. Ed., 2022, 61, e202201750.
10. For meta-C–H functionalization by either steric or electronic influences: (a) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi and J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 390–391; (b) J.-Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka Jr and M. R. Smith III, Science, 2002, 295, 305–308; (c) Y. Saito, Y. Segawa and K. Itami, J. Am. Chem. Soc., 2015, 137, 5193–5198; (d) R. Bisht and B. Chattopadhyay, J. Am. Chem. Soc., 2016, 138, 84–87; (e) B. Ramadoss, Y. Jin, S. Asako and L. Iles, Science, 2022, 375, 658–663; (f) R. J. Phipps and M. J. Gaunt, Science, 2009, 323, 1593–1597; (g) Y.-H. Zhang, B.-F. Shi and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 5072–5074 . For an example using a traceless directing group relay strategy: ; (h) J. Luo, S. Preciado and I. Larrosa, J. Am. Chem. Soc., 2014, 136, 4109–4112.
11. K. A. Duggan, WO2016/145479A1, 2016.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4sc03802a

---