Nickel-Catalyzed Enantioselective C(sp 3 )–H Arylation of Ketones with Aryl Ethers via Selective C Ar –O Cleavage to Construct All-Carbon Quaternary Stereocenters

Abstract

Open AccessCCS ChemistryCOMMUNICATION5 Sep 2022Nickel-Catalyzed Enantioselective C(sp3)–H Arylation of Ketones with Aryl Ethers via Selective CAr–O Cleavage to Construct All-Carbon Quaternary Stereocenters Mingliang Li and Jun (Joelle) Wang Mingliang Li Department of Chemistry, Southern University of Science and Technology (SUSTech), Shenzhen 518055 Google Scholar More articles by this author and Jun (Joelle) Wang *Corresponding author: E-mail Address: [email protected] Department of Chemistry, Hong Kong Baptist University, Kowloon, Hong Kong 999077 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202101611 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We designed thenickel-catalyzed enantioselective C(sp3)–H arylation of ketones with phenol-derived aryl pyrimidyl ethers via selective cleavage of the C(aryl)–O bond to construct all-carbon quaternary stereocenters. This method exhibits good functional group compatibility and broad substrate scope. Drug molecule donepezil can directly transform into corresponding highly optically pure derivatives with this developed methodology. Mechanistic studies reveal that C(aryl)–O cleavage of aryl pyrimidyl ether probably proceeded by means of an anionic organo-Ni(0) intermediate. Download figure Download PowerPoint Introduction Quaternary stereocenters extensively exist in natural products, pharmaceuticals, and other bioactive molecules.1–4 Recently, more and more attention has been dedicated to the development of transition metal-catalyzed methodology to synthesize all-carbon quaternary stereocenters, which have broader structural diversity and particular conformational constraints compared with tertiary carbon stereocenters.1–7 Construction of such highly substituted carbon centers is a difficult but important challenge due to the steric impediment for C–C bond formation, especially for controlling enantioselectivity. Although remarkable progress has been achieved in the catalytic enantioselective synthesis of quaternary stereocenters bonded by four carbon substituents,1–14 this issue remains a challenge for the construction of more interesting molecules. Aryl-substituted all-carbon quaternary stereocenters as an important part of chiral quaternary carbon centers frequently occur in drugs and bioactive molecules, and their absolute configuration often greatly influences the pharmacodynamic activity of related bioactive molecules. Therefore, developing methods to construct aryl-substituted chiral quaternary stereocenters is an attractive topic for the organic chemist. In 1992, Ashimori and Overman15 developed a seminal work on the palladium-catalyzed intramolecular asymmetric Heck reaction for the synthesis of chiral spirooxindoles with quaternary stereocenters. Subsequently, the transition metal-catalyzed asymmetric Heck reaction,16–18 conjugate addition,19,20 coupling of tertiary carbon radicals,21 and α-arylation of carbonyl and nitrile derivatives22–32 have been well developed for the synthesis of aryl-substituted quaternary stereocenters (Scheme 1a). However, nickel-catalyzed enantioselective α-arylation of carbonyl compounds for the construction of quaternary carbon centers has only been reported in limited examples (Scheme 1b).27–30 In 2002, Spielvogel and Buchwald27 developed a nickel-catalyzed enantioselective α-arylation of α-substituted γ-butyrolactones utilizing the accelerating effect of Zn(II) salts. Later, nickel-catalyzed asymmetric α-arylation reactions of cyclic ketones with aryl chlorides or bromides were achieved by the Hartwig and Stanley groups.28,30 So far, there was only one example of nickel-catalyzed asymmetric C(sp3)–H arylation of cyclic carbonyl compounds with phenol derivatives (aryl pivalates) reported by Martin and co-workers.29 Considering readily accessible and diverse substituted phenolic compounds from natural sources, we wish to develop a novel phenol-derived arylating agent for nickel-catalyzed asymmetric C(sp3)–H arylation to deliver aryl-substituted chiral quaternary carbon centers. Scheme 1 | Transition metal-catalyzed construction of aryl-substituted quaternary stereocenters. Download figure Download PowerPoint Undoubtedly, phenol derivatives are naturally abundant aromatic feedstocks and are preferable from the standpoint of environmental conservation compared with aryl halides or boron compounds. Since a seminal work on nickel-catalyzed cross-coupling of aryl ethers with aryl magnesium bromides was reported by Wenkert and co-workers in 1979,33 transition metal-catalyzed C(sp2)–O cleavage of phenol derivatives, such as aryl triflates, tosylates, sulfamates, phosphates, carbonates, carbamates, carboxylates, and ethers, has been widely developed for constructing C–C and C–X (X= N, B, Si, P, Sn, etc.) bonds.34–36 Compared with other phenol derivatives, less-activated aryl ethers (including aryl methyl ethers, diaryl ethers, aryl pyridyl or pyrimidyl ethers, aryl silyl ethers) are more ideal substrates in terms of availability, stability, safety, and atomic efficiency.35 However, the high bond dissociation energy of the C(aryl)−O bond constrains the development of catalytic functionalization of aryl ethers.37 So far, transition metal-catalyzed (e.g., Ni, Fe, Rh, Ru, etc.) cross-coupling reactions of aryl methyl or pyridyl ethers with organometallic reagents, boron reagents, amines, and hydrosilanes have been well developed,38–42 but catalytic C(sp3)–H arylation reactions are rarely reported, let alone the asymmetric version of C(sp3)–H arylation with aryl ethers. Furthermore, there are no examples of transition metal-catalyzed C(sp2)–O cleavage of aryl pyrimidyl ethers, though they are more environmentally friendly aromatic feedstocks compared with pyridyl ethers. Herein, we describe the first example of nickel-catalyzed asymmetric arylation of α-substituted ketones with aryl pyrimidyl ether to construct aryl-substituted quaternary all-carbon stereocenters (Scheme 1c). Results and Discussion We initially investigated the nickel-catalyzed enantioselective C(sp3)–H arylation with 2-methyl-2,3-dihydro-1H-inden-1-one ( 1a) and 2-(4-methoxyphenoxy)pyridine ( 2a) (Table 1). After screening a series of chiral ligands [Table 1 (entries 1–10) and Supporting Information Table S1], (R, SFC)-Josiphos SL-J005-1 ( L10) delivered the desired product in 32% yield and 67% ee in the presence of Ni(cod)2 and NaOtBu in toluene. The reaction yield and ee value were improved to 63% and 71%, respectively, by adjusting solvent, reaction temperature, and time ( Supporting Information Table S2). Interestingly, the addition of chiral acids effectively improved the enantioselectivity, which was probably derived from ligand exchange of chiral anion with pyridin-2-olate in nickel(II) intermediate formed by the oxidative addition of aryl ethers to nickel catalyst. After exploring an array of chiral phosphoric or amino acids, we found that N-(tert-butoxycarbonyl)-l-phenylalanine (N-Boc-l-Phe-OH) provided the best result ( Supporting Information Table S3). The reaction ee value was slightly increased with the addition of Zn(OTf)2, probably caused by the coordination of Zn2+ with pyridin-2-olate or carbonyl of ketones ( Supporting Information Table S4). When 2-(4-methoxyphenoxy)pyrimidine 2a-1 was used instead of 2a, the reaction yield was further improved (Table 1, entry 15). Finally, the desired product 3a was afforded in 75% yield and 92% ee with 2-(4-methoxyphenoxy)pyrimidine as the arylating agent in the presence of Ni(cod)2 (10 mol %), L10 (10 mol %), N-Boc-l-Phe-OH (10 mol %), Zn(OTf)2 (20 mol %), and NaOtBu (1.5 equiv) in p-xylene. Almost no product was obtained when the 2-pyrimidyl moiety in aryl ether was replaced by other heteroaryl, such as quinolin-2-yl, 2-(6-methyl)pyridyl, 6-methyl-2-pyridyl, 2-methoxy-6-pyridyl, or 2-fluoro-6-pyridyl ( Supporting Information Table S5). Table 1 | Optimization of Reaction Conditionsa Entry Ligand Additive (mol %) Yield (%)b ee (%)c 1 L1 None 20 15 2 L2 None 24 42 3 L3 None 44 11 4 L4 None 28 46 5 L5 None 20 3 6 L6 None Trace — 7 L7 None 24 15 8 L8 None Trace — 9 L9 None 20 27 10 L10 None 32 67 11d L10 None 63 71 12d L10 N-Boc-l-Phe-OH (10) 60 85 13d L10 N-Boc-l-Phe-OH (10)Zn(OTf)2 (20) 60 90 14e L10 N-Boc-l-Phe-OH (10)Zn(OTf)2 (20) 54 89 15e,f L10 N-Boc-l-Phe-OH (10)Zn(OTf)2 (20) 75 92 aReaction conditions: Ni(cod)2 (10 mol %) and ligand (10 mol %) in dry toluene (0.5 mL) were stirred at RT for 20 min under argon. 1a (0.1 mmol), 2a (0.2 mmol), additive, and NaOtBu (0.15 mmol) were then added. The mixture was stirred at 120 °C for 24 h. bIsolated yields. cDetermined by chiral HPLC. dp-Xylene (0.5 mL), 130 °C, 48 h. eReaction was conducted on a 0.2 mmol scale with respect to 1a. f2-(4-Methoxyphenoxy)pyrimidine 2a-1 (0.4 mmol) was used instead of 2a. With the optimized reaction conditions in hand, we next explored the scope of aryl pyrimidyl ethers 2 with 2-methyl-2,3-dihydro-1H-inden-1-one 1a. As described in Scheme 2, a series of aryl pyrimidyl ethers with electron- or electron-withdrawing groups (e.g., OMe, OBn, NMe2, Ph, Me, F, CF3, CN, and CO2Me) on the para-position of aryl rings all proceeded well to deliver corresponding products in good yield and excellent ee values ( 3a– 3j). The substitute on the meta-position of aryl rings in aryl pyrimidyl ethers did not influence the asymmetric C(sp3)–H arylation ( 3k– 3o). Desired products could also be afforded in good yields and ee values with 2-naphthyl pyrimidyl ethers with functional groups (e.g., Ph, OMe, CN, and CO2Me) on the 6-position of the naphthyl ring ( 3p– 3t). The absolute configuration of the major arylated products was determined to be (R)- by single-crystal X-ray analysis of 3s ( Supporting Information Figure S1, CCDC 2058470). Interestingly, heteroaryl pyrimidyl ethers could also effectively couple with 1a to provide corresponding products in high yields and excellent ee values ( 3u and 3v), which could undergo further functionalization of heteroaryl moieties to provide novel chiral derivatives with interesting bioactivity considering that quinolinyl and indolyl frameworks widely exist in natural products, drugs, and other bioactive molecules.43,44 Scheme 2 | Substrate scope of aryl pyrimidyl ethers. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Ni(cod)2 (10 mol %), L10 (10 mol %), N-Boc-l-Phe-OH (10 mol %), Zn(OTf)2 (20 mol %), NaOtBu (0.3 mmol), p-Xylene (1.0 mL), 130 °C, 48 h, isolated yields; ee values are determined by HPLC. Download figure Download PowerPoint Next, we examined the scope of ketones with pi-extended aromatic 2-naphthyl pyrimidyl ethers 2. As shown in Scheme 3, various 2-methyl-2,3-dihydro-1H-inden-1-one derivatives with substituent (Me, F, and OMe) on the 5- or 6-position of aryl rings all proceeded smoothly to afford desired products in high yield and excellent ee values ( 4a– 4f). 2-Alkyl, benzyl, or allyl substituted 2,3-dihydro-1H-inden-1-one derivatives were all quite compatible with the reaction conditions ( 4g– 4l). The ester or allyl group in product 4k or 4l provided the opportunity for further transformation. Strangely, the reaction ee value was obviously decreased with 2-methylbenzofuran-3(2H)-one ( 4m), which was probably caused by the coordination of oxygen with chiral nickel intermediate. Except for five-member cyclic ketones, 2-methyl-3,4-dihydronaphthalen-1(2H)-one 1n could also couple well with 2-naphthyl pyrimidyl ethers 2 to provide desired products. Scheme 3 | Substrate scope of ketones. Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Ni(cod)2 (10 mol %), L10 (10 mol %), N-Boc-l-Phe-OH (10 mol %), Zn(OTf)2 (20 mol %), NaOtBu (0.3 mmol), p-Xylene (1.0 mL), 130 °C, 48 h, isolated yields; ee values are determined by chiral HPLC. Download figure Download PowerPoint Late-stage functionalization (LSF) of complex molecules is a highly powerful and effective methodology to achieve desired chemoselective transformation without the installation of a functional group.45,46 Notably, transition metal-catalyzed direct C–H functionalization is a very popular method for LSF. Donepezil is an acetylcholinesterase inhibitor for improving cognition and global function in patients with Alzheimer’s and vascular dementia via modulation of acetylcholine receptors and downstream inflammatory response.47 We wish to apply developed asymmetric arylation of ketones to the LSF of donepezil to provide highly optically pure derivatives, which might have better pharmacodynamic activity compared with racemic donepezil compounds. Under the standard reaction conditions, donepezil could couple well with aryl or heteroaryl pyrimidyl ether to deliver corresponding products in medium yield and excellent ee values, which provides opportunity for exploring the bioactivity in the following work (Scheme 4a). To examine the efficacy of the reaction, a gram-scale reaction was carried out with 4 mmol of 2-methyl-2,3-dihydro-1H-inden-1-one 1a, and the product 3q was afforded in 93% yield (1.30 g) and 92% ee with the standard reaction conditions (Scheme 4b). Scheme 4 | LSF of donepezil and gram-scale reaction. Download figure Download PowerPoint To gain insight into the mechanism, we first carried out the ligand exchange experiment (Scheme 5a). With stoichiometric amounts of Ni(cod)2 (1.0 equiv) and diphosphine ligand L10 (1.0 equiv) at room temperature, complex Ni( L10)(cod) was obtained in almost quantitative yield, which was confirmed by 1H NMR, 31P NMR, and high-resolution mass spectrometry (HRMS). Complex Ni(0)( L10)(cod) was easily oxidized by air. Unfortunately, 2-(naphthalen-2-yloxy)pyrimidine did not undergo oxidative addition with complex Ni( L10)(cod) to provide nickel(II) intermediate at 90 or 120 °C, just delivering different nickel(0) complex formed by nickel catalyst and ligand L10, which could also be obtained by the treatment of Ni(cod)2 (1.0 equiv) and L10 (1.0 equiv) in C6D6 at 120 °C (Scheme 5b). It suggested that the C(aryl)−O cleavage of aryl pyrimidyl ethers was probably achieved by an anionic organo-Ni(0) species formed by enolate anion with nickel complex, rather than complex Ni( L10)(cod).48–50 Scheme 5 | Mechanism research. Download figure Download PowerPoint Based on the aforementioned mechanistic research and related reports,42,48–50 the plausible mechanism of the asymmetric C(sp3)–H arylation was proposed (Scheme 6). Initially, chiral phosphine ligand coordinated with Ni(cod)2 to deliver nickel complex I and was characterized by NMR and HRMS. Then complex I underwent ligand exchange with enolate anion and aryl pyrimidyl ethers to afford anionic organo-Ni(0) intermediate II, which generated nickel(II) complex III via an oxidative addition process. Next, nickel(II) intermediate IV was obtained by ligand dissociation of intermediate III to release pyrimidin-2-olate in the absence of chiral amino acids and Zn(OTf)2 (path a). Finally, reductive elimination of intermediate IV delivered the desired products, and the resultant nickel(0) complex coordinated with cycloocta-1,5-diene (cod) to regenerate intermediate I to complete the catalytic cycle. Also, intermediate III can transform into anion nickel(II) complex V by ligand exchange with the addition of chiral amino acids and Zn(OTf)2 (path b). Subsequently, desired products were afforded by reductive elimination of intermediate V, and the result anion nickel(0) complex VI underwent ligand exchange with cycloocta-1,5-diene or enolate anion to provide Intermediate I or II to accomplish the catalytic cycle. Scheme 6 | Plausible mechanism. Download figure Download PowerPoint Conclusion We have succeeded in developing the first nickel-catalyzed asymmetric C(sp3)–H arylation of ketones with phenol-derived aryl pyrimidyl ethers via selective cleavage of the C(aryl)–O bond to construct all-carbon quaternary stereocenters. A series of ketones and aryl pyrimidyl ethers with different functional groups react well to afford desired products in good yields and ee values. Further, drug molecule donepezil directly transformed into desired high optically pure derivatives with our developed methodology. Mechanistic studies reveal that C(aryl)–O cleavage of aryl pyrimidyl ether probably proceeded by means of the anionic organo-Ni(0) intermediate. Supporting Information Supporting Information is available and includes general remarks, optimization of the reaction conditions, general procedure for the asymmetric C(sp3)-H arylation of ketones, characterization of products, late-stage functionalization of donepezi, procedure for gram-scale reaction, mechanism research, and X-ray crystallographic analysis. Conflict of Interest The authors declare no competing financial interests. Funding Information We gratefully acknowledge the National Natural Science Foundation of China (no. NSFC 21902072) and the Guangdong Innovative Program (no. 2019BT02Y335) for their financial support.