Chromium(II)-catalyzed enantiolective arylation of ketones Gang Wang1,2, Shutao Sun2, Ying Mao2, Zhiyu Xie2 and Lei Liu*1,2,3
Abstract
The chromium-catalyzed enantiolective addition of carbo halides to carbonyl compounds is an important transformation in organic synthesis. However, the corresponding catalytic enantiolective arylation of ketones has not been reported to date. Herein, we report the first Cr-catalyzed enantiolective addition of aryl halides to both arylaliphatic and aliphatic ketones with high enan-tiol
ectivity in an intramolecular version, providing facile access to enantiopure tetrahydronaphthalen-1-ols and 2,3-dihydro-1H-inden-1-ols containing a tertiary alcohol.
Introduction
Catalytic enantiolective carbon–carbon bond formation reac-tions have achieved enormous development during the last few decades as a conquence of the growing demand for enan-tiopure compounds in modern industry, especially the pharma-ceutical industry. The chromium (Cr)-catalyzed enantiolec-tive addition of carbo halides to carbonyl compounds is one of the most reliable methods in organic chemistry for chemolec-tive and structurally diver synthesis [1-9]. To date, the Cr-cat-alyzed enantiolective carbonyl addition reactions mainly focud on allylation, propargylation, alkenylation and alkyl-ation of aldehydes [10,11]. Since the first example of enantio-lective allylation of aldehydes catalyzed by a Cr(II)–salen com-plex in 1999 by Cozzi and co-workers [12], veral elegant cat-alytic enantiolective allylation and propargylation reactions have been developed by the groups of Nakada [13,14], Berkesl [15], Kishi [16], Sigman [17], Yamamoto [18], Guiry [19], Chen [20], Gade [21], White [22], and Zhang [23-25], re-spectively. The alkenylation and alkylation reactions were mainly explored by the Kishi group [26-30], and they estab-lished a toolbox approach to arch for the specific ligand with a given substrate in the Cr-cata
lyzed process [28]. They suc-cessfully applied the method to the natural product total synthe-sis like halichondrin B and norhalichondrin B, and in the sub-quent pharmaceutical study, finally leading to the discovery of the anticancer drug Eribulin [31-35]. However, to our know-ledge, the Cr-catalyzed enantiolective arylation of carbonyl
compounds has rarely been explored. On the other hand, most of the reactions focud on aldehyde components, while asym-metric addition to ketones remains a big challenge probably due to the decread reactivity and lectivity [36,37]. A break-through was made by the Sigman group who reported the cata-lytic enantiolective addition of allylic bromides and propargyl halides to arylaliphatic ketones using oxazoline ligands with high enantiolectivity (up to 95% ee) [38-41]. After that, the Chen group also disclod enantiolective allylation of ke-tones using spirocyclic chiral borate and chiral bipyridyl alcohol ligands with the ee value ranging from 27% to 97% [42,43]. However, as far as we know, a Cr-catalyzed enantiolective arylation of ketones has never been reported to date [44]. Tetrahydronaphthalen-1-ol bears a chiral tertiary alcohol center and is a common structural motif in numerous biologically active natural products and clinical drugs [45]. The method to prepare the compounds through intramolecular arylation of ketones would be highly desired. Herein, we report the first Cr-catalyzed enantiolective arylation of ketones in an intra-molecular version.
Results and Discussion
Initially, the Cr-catalyzed asymmetric intramolecular arylation of arylaliphatic ketone 5-(2-iodophenyl)pentan-2-one (1a) was lected as the model reaction for optimization employing Kishi’s oxazoline/sulfonamides as the chiral ligands. A ries of oxazoline/sulfonamide ligands (L1–L8) were tested and the results were summarized in Table 1. Four subgroups of R1 were studied (entries 1–4, Table 1) and isopropyl substituted oxa-zoline proved to be the best ligand with a 42% ee. Afterwards, R2 (Table 1, entries 2, 5 and 6) and R3 (Table 1, entries 6–8) substituents were also examined, and L8 bearing a methyl
group in both R2 and R3 gave the best enantiocontrol. The sol-vent effect was then investigated, and 1,2-dimethoxyethane (DME) was identified to be the best choice (Table 1, entries 8–10). Lowering the reaction temperature was found to be bene-ficial for improving the enantiolectivity, and when the reac-tion was performed at −20 °C, expected 2a was isolated in 81% yield with 97% ee (Table 1, entries 10–13). Aryl bromide proved to be an inferior coupling component, providing 2a in 35% yield and 70% ee (Table 1, entry 14).
With the optimized conditions in hand, the scope of the ketone component was first explored (Scheme 1). Aliphatic ketones with (longer) alkyl chain such as ethyl (1b) and n-hexyl ke-tones (1c), were also tolerated albeit with slightly decread
yield and lectivity. The asymmetric arylation of various arylaliphatic ketones also went smoothly (1d–h). Phenyl ke-tone 1d and ketones with electron-withdrawing groups in differ-ent substituent patterns gave the expected products with good enantiocontrol, while the enantiolectivity for ketone 1e bear-ing an electron-donating group decread. The mild process exhibited excellent functional group tolerance, with chloride (2f), fluoride (2g), and CF3 moieties (2h) well tolerated for further manipulation [46,47]. Heteroaryl ketones such as furan-substituted ketone (1i) were also suitable substrate, giving prod-uct 2i in 78% ee. The scope of the aryl halide component was next explored (1j–l). Aryl halides bearing different substituent patterns were tolerated giving the tetrahydronaphthalen-1-ols with good ee values. When 4-(2-iodophenyl)butan-2-one (1m) was ud, enantiopure indan-1-ol was obtained in 70% yield and 82% ee.
Conclusion
In summary, we have developed the first Cr-catalyzed enantio-lective arylation of ketones in an intramolecular version using oxazoline/sulfonamide L8 as the catalyst. Both aliphatic and arylaliphatic ketones proceeded smoothly, providing corre-sponding tetrahydronaphthalen-1-ols bearing a tertiary alcohol center with good enantiolectivities (up to 97% ee).
Experimental
General procedure for the chromium(II) catalyzed enantio-lective arylation of ketones: The solution of L8 (0.25 equiv, 0.025 mmol), proton sponge (0.25 equiv, 0.025 mmol) and CrCl2 (0.23 equiv, 0.023 mmol) in DME (1.0 mL) was stirred at room temperature in a glove-box for 1 h. Then the substrate 1 (1.0 equiv, 0.1 mmol), LiCl (2.0 equiv, 0.2 mmol), Mn powder (3.0 equiv, 0.3 mmol), NiCl2·DMP (0.12 equiv, 0.012 mmol) and Zr(CP)2Cl2 (2.0 equiv, 0.2 mmol) were added successively and the mixture was stirred at indicated temperature for 24 h. After that, the mixture was filtered through a short pad of celite and purified by flash chromatography using silica gel or alumina (200–300 mesh) to give the product 2.
Supporting Information
Supporting Information File 1
Experimental procedures, analytical data for products, copies of NMR spectra and HPLC chromatograms.
[www.beilstein-journals/bjoc/content/ supplementary/1860-5397-12-275-S1.pdf]
Acknowledgements
白首成约
We thank the National Science Foundation of China (21472112), Fok Ying Tung Education Foundation (151035),the Program for New Century Excellent Talents in University (NCET-13-0346), Shenzhen Strategic Emerging Industry De-velopment Special Funds (JCYJ20150430160921949), the Shandong Science Fund for Distinguished Young Scholars (JQ201404), and the Fundamental Rearch Funds of Shan-dong University (2015JC035) for financial support.
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