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Palladium-Catalyzed Synthesis of Β-Hydroxy Compounds Via A Chemical Science EDGE ARTICLE View Article Online View Journal | View Issue Palladium-catalyzed synthesis of b-hydroxy compounds via a strained 6,4-palladacycle from Cite this: Chem. Sci., 2020, 11,7260 directed C–H activation of anilines and C–O All publication charges for this article have been paid for by the Royal Society insertion of epoxides† of Chemistry a b b Raju S. Thombal, Taisiia Feoktistova, Gisela A. Gonzalez-Montiel,´ Paul H.-Y. Cheong *b and Yong Rok Lee *a A palladium-catalyzed C–H activation of acetylated anilines (acetanilides, 1,1-dimethyl-3-phenylurea, 1- phenylpyrrolidin-2-one, and 1-(indolin-1-yl)ethan-1-one) with epoxides using O-coordinating directing groups was accomplished. This C–H alkylation reaction proceeds via formation of a previously unknown 6,4-palladacycle intermediate and provides rapid access to regioselectively functionalized b-hydroxy products. Notably, this catalytic system is applicable for the gram scale mono-functionalization of acetanilide in good yields. The palladium-catalyzed coupling reaction of the ortho-C(sp2) atom of O- Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Received 11th March 2020 coordinating directing groups with a C(sp3) carbon of chiral epoxides offers diverse substrate scope in Accepted 20th June 2020 good to excellent yields. In addition, further transformations of the synthesized compound led to DOI: 10.1039/d0sc01462a biologically important heterocycles. Density functional theory reveals that the 6,4-palladacycle leveraged À rsc.li/chemical-science in this work is significantly more strained (>10 kcal mol 1) than the literature known 5,4 palladacycles. Introduction synthons and can be readily converted into biologically impor- tant heterocycles such as indoles.6 Transformative transition metal catalyzed coupling reactions The C–H functionalization of arenes with various coupling This article is licensed under a concomitant with C–H functionalization and epoxide C–O partners has become a promising tool for synthetic chemists.7 insertion have recently been reported in the literature.1–3 The Particularly, epoxides are widely used as alkylating reagents and key enabling structural feature in these reactions is the use of building blocks in the construction of organic molecules via Open Access Article. Published on 22 June 2020. Downloaded 10/7/2021 3:35:03 PM. strongly coordinating or bi-dentate directing groups. These C–H bond functionalization.8 In the past few decades, signi- pioneering reports all hinge on the use of 5,4-metallacycles cant progress has been made on the regioselective ring-opening (Scheme 1).1–4 Surprisingly, functionalization via 6,4-metalla- of epoxides using a variety of nucleophiles on different catalytic cycles is unknown in the literature. We reveal the rst examples platforms.9 The construction of C–C bonds by the opening of of successfully accessing and leveraging 6,4-palladacycles.5 Specically, we report a palladium-catalyzed regioselective ortho-functionalization of anilines with O-coordinating direct- ing groups, such as acetanilides, 1-phenylpyrrolidin-2-one, and 1-(indolin-1-yl)ethan-1-one, with epoxides (Scheme 1). We report the density functional theory study of the complete catalytic cycle and also reveal that the 6,4-palladacycle is more strained than the literature-known 5,4 palladacycles. Impor- tantly, the synthesized b-hydroxy compounds are versatile aSchool of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea. E-mail: [email protected] bDepartment of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331, USA † Electronic supplementary information (ESI) available: Experimental procedures, characterization data, computational details and X-ray crystallographic structure Scheme 1 Transition metal catalyzed C–H/X functionalization and and data for 6b-S. CCDC 1981280. For ESI and crystallographic data in CIF or alkylation with epoxides (top) and known 5,4-metallacycle vs. the other electronic format see DOI: 10.1039/d0sc01462a current strategy – 6,4-metallacycle (bottom). 7260 | Chem. Sci.,2020,11, 7260–7265 This journal is © The Royal Society of Chemistry 2020 View Article Online Edge Article Chemical Science epoxides with aryl nucleophiles has played an important role in products (entries 1–5, Table 1). We also attempted the reaction 10 organic synthesis. Generally, the signi cant ring strain of using several palladium catalysts such as Pd(TFA)2, PdCl2, – epoxides enhances their susceptibility to ring-opening with Pd(OAc)2, and PdCl2(PPh3)4 using HFIP as solvent (entries 6 9, 11 a wide array of electron-rich species. In this context, several Table 1). Among them, the 10 mol% of the Pd(OAc)2 catalyst enantioselective and regioselective methods have been devel- provided the highest yield (64%). Several solvents were next oped with the nucleophilic attack of –N, –O, and –halo nucle- screened. The reactions using 1,2-dichloroethane, CH3CN, tri- ophiles using the stoichiometric amount of promoters. uoroethanol, and tetrahydrofuran as solvents, afforded the Therefore, the development of a catalytic version of these types desired product 3a in lower yields, while AcOH failed to produce of reactions for the functionalization at a specic position is the desired product (entries 10–14, Table 1). With 1 equiv. of still highly desirable. acidic additives PivOH and 1-AdCO2H, 3a was produced in 31% Transition-metal-catalyzed direct utilization of epoxides has and 27% yields, respectively (entries 15 and 16, Table 1). With 1 received much attention in organic synthesis in the past few equiv. of basic additives NaOAc or Cs2CO3, 3a was not produced decades.12–15 The reported representative modications include at all (entries 17 and 18, Table 1). Interestingly, increasing the the nickel-catalyzed opening of epoxides with aryl halides,16 and loading of AcOH to 3 equiv. produced the best yield (79%, entry Li/Cu-catalyzed synthesis of enantiopure starting materials 19, Table 1). However, decreasing the amount of AcOH to 0.5 (Scheme 1).17 equiv. provided 3a in a lower yield (41%, entry 20, Table 1). Overall, acidic additives were found to be superior to basic additives, probably due to their participation in the C–H acti- Results and discussion vation step. Increasing or decreasing the amount of the To optimize the reaction conditions, we rst examined the Pd(OAc)2 catalyst did not improve the yield of 3a (entries 21 and reaction between N-phenylacetamide 1a and 2-(phenoxymethyl) 22, Table 1). Importantly, the control reaction without the oxirane 2a using several catalysts and additives (Table 1). The Pd(OAc)2 catalyst failed to produce 3a. The structure of 1 – Creative Commons Attribution-NonCommercial 3.0 Unported Licence. synthesized compound 3a was identi ed by H NMR there is initial attempts in the presence of 10 mol% of Ni(COD)2, a characteristic singlet signal of the NH-proton of the acetani- Rh2(OAc)4, Co(OAc)2, [RuCl2(p-cymene)]2, and Cu(OAc)2 and 1 d equiv. of AcOH in HFIP at 60 C for 24 h did not provide any lide amide at 9.23 ppm and newly generated methine proton Table 1 Optimization of reaction conditionsa This article is licensed under a Open Access Article. Published on 22 June 2020. Downloaded 10/7/2021 3:35:03 PM. Entry Catalyst (mol%) Additives (equiv.) Solvent Temp. (C) Time (h) Yieldb (%) 1 Ni(COD)2 (10) AcOH (1) HFIP 60 24 00 2Rh2(OAc)4 (10) AcOH (1) HFIP 60 24 00 3 Co(OAc)2 (10) AcOH (1) HFIP 60 24 00 4 [RuCl2(p-cym)]2 (10) AcOH (1) HFIP 60 24 00 5 Co(OAc)2 (10) AcOH (1) HFIP 60 24 00 6 Pd(TFA)2 (10) AcOH (1) HFIP 60 24 42 7 PdCl2 (10) AcOH (1) HFIP 60 24 38 8 Pd(OAc)2 (10) AcOH (1) HFIP 60 24 64 9 PdCl2(PPh3)4 (10) AcOH (1) HFIP 60 24 54 10 Pd(OAc)2 (10) AcOH (1) DCE 80 48 10 11 Pd(OAc)2 (10) AcOH (1) CH3CN 70 48 08 12 Pd(OAc)2 (10) AcOH (1) TFE 70 48 10 13 Pd(OAc)2 (10) — AcOH 60 48 00 14 Pd(OAc)2 (10) AcOH (1) THF 60 48 15 15 Pd(OAc)2 (10) PivOH (1) HFIP 60 24 31 16 Pd(OAc)2 (10) 1-AdCO2H (1) HFIP 60 24 27 17 Pd(OAc)2 (10) NaOAc (1) HFIP 60 24 00 18 Pd(OAc)2 (10) Cs2CO3 (1) HFIP 60 24 00 19 Pd(OAc)2 (10) AcOH (3) HFIP 60 24 79 20 Pd(OAc)2 (10) AcOH (0.5) HFIP 60 24 41 21 Pd(OAc)2 (20) AcOH (3) HFIP 60 24 79 22 Pd(OAc)2 (05) AcOH (3) HFIP 60 24 66 23 — AcOH (3) HFIP 60 24 00 a Reaction conditions: 1a (1 mmol), 2a (1 mmol), catalyst and additives in solvent (3.0 mL) for 24 h. b Isolated yields. This journal is © The Royal Society of Chemistry 2020 Chem. Sci.,2020,11, 7260–7265 | 7261 View Article Online Chemical Science Edge Article at d 4.25 ppm. The 13C NMR spectrum showed a characteristic signal of the amide carbonyl at d 168.9 ppm. The structure was further conrmed by single-crystal X-ray diffraction analysis of the structurally related compound 6b-S. In order to explore the mechanism of this reaction, we – u 18 computed the entire catalytic cycle using DFT B97XD /6- Scheme 2 Isodesmic reaction of 6,4-Palladacycle-VI and the analo- 31G* (ref. 19) & LANL2DZ20/PCM21 (acetone)22 at 60 C with gous 5,4-palladacycle derived from 2-phenylpyridine. Gaussian 16. All possible ligand coordination spheres around Pd, involving acetate, acetic acid, acetanilide 1a, and methyl epoxide for all pathways were considered. This reaction can rst 6,4-palladacycle is higher in energy and more strained than the – À1 proceed via Pd(OAc)2 C H activation of acetanilide 1a or literature known 5,4 palladacycles by >10 kcal mol .
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