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Communication

Asymmetric Synthesis of Tertiary α -Hydroxyketones by Enantioselective Decarboxylative Chlorination and Subsequent Nucleophilic Substitution

by
Mei Kee Kam
,
Akira Sugiyama
,
Ryouta Kawanishi
and
Kazutaka Shibatomi
*
Department of Applied Chemistry and Life Science, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(17), 3902; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25173902
Submission received: 27 July 2020 / Revised: 17 August 2020 / Accepted: 20 August 2020 / Published: 27 August 2020
(This article belongs to the Special Issue Feature Papers to Celebrate Molecules Reaches 20,000 Articles Milestone)
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Abstract

:
Chiral tertiary α-hydroxyketones were synthesized with high enantiopurity by asymmetric decarboxylative chlorination and subsequent nucleophilic substitution. We recently reported the asymmetric decarboxylative chlorination of β-ketocarboxylic acids in the presence of a chiral primary amine catalyst to obtain α-chloroketones with high enantiopurity. Here, we found that nucleophilic substitution of the resulting α-chloroketones with tetrabutylammonium hydroxide yielded the corresponding α-hydroxyketones without loss of enantiopurity. The reaction proceeded smoothly even at a tertiary carbon. The proposed method would be useful for the preparation of chiral tertiary alcohols.

1. Introduction

Chiral tertiary alcohols are important synthetic intermediates for the preparation of medicinally relevant compounds because numerous biologically active compounds contain the tertiary hydroxy moiety in their structure [1,2,3,4,5,6]. Using oxidative α-hydroxylation of carbonyl compounds is a useful method for introducing a hydroxy group onto a chiral carbon center. However, there are not many efficient methods for the catalytic asymmetric version of the α-hydroxylation of carbonyl compounds to form chiral tertiary alcohols, including the hydroxylation of enolates or enol ethers [7,8,9,10,11,12,13,14,15]. Recently, our research group developed a catalytic enantioselective decarboxylative chlorination of β-ketocarboxylic acids 1 using N-chlorosuccinimide (NCS) to afford tertiary α-chloroketones 2 with high enantioselectivity [16]. Moreover, the SN2 reaction of the resulting α-chloroketones proceeded smoothly with strong nucleophiles, such as sodium azide and alkyl thiols, even at a tertiary carbon center [16,17,18,19,20,21,22,23]. Inspired by these results, we successfully synthesized chiral tertiary α-hydroxyketones 3 by the enantioselective decarboxylative chlorination of β-ketocarboxylic acids and subsequent nucleophilic substitution with a hydroxide ion as the nucleophile (Scheme 1). The method would be a good alternative to the direct α-hydroxylation of simple ketones.

2. Results and Discussion

First, we attempted the nucleophilic substitution of tertiary α-chloroketones 2 with a hydroxide ion. The racemic form of tetralone-derived α-chloroketone 2a was chosen as a model substrate. The reaction of 2a with inorganic hydroxides led to the low conversion of the starting compound and yielded only trace amounts of the desired α-hydroxyketone 3a (Table 1; entries 1 and 2). Although the use of tetrabutylammonium fluoride (TBAF) hydrate improved the conversion of the starting compound, 3a was obtained in very poor yield, along with 38% of 2-allyl-1-naphthol (4a) as a by-product (entry 3). Compound 4a was probably generated by the elimination of hydrogen chloride from 2a and subsequent aromatization. Fortunately, 3a was obtained in good yield (68%), along with 4a in a 14% yield, when tetrabutylammonium hydroxide (TBAOH) was employed as the nucleophile (entry 4). Screening of various solvents revealed that acetonitrile was the best choice for the reaction.
Next, we prepared optically active tertiary α-chloroketones 2 for the asymmetric synthesis of α-hydroxyketone 3 by the enantioselective decarboxylative chlorination of β-ketocarboxylic acids 1 in the presence of chiral primary amine catalyst C1 [16,24], according to our previous report [16]. As shown in Figure 1, a series of chiral α-chloroketones 2, including tetralone derivatives 2a–2e, 4-chromanone derivative 2f, indanone derivative 2g, and cyclohexanone derivative 2h, were obtained in high yields, with moderate-to-high enantiopurity. It should be mentioned that the formation of Favorskii rearrangement product was not observed in the reaction of 2h [22,25]. Then, we attempted the SN2 reaction of optically active 2 with tetrabutylammonium hydroxide under the optimized conditions. Accordingly, 2 was allowed to react with 1.5 equiv. of TBAOH (40% in water) in acetonitrile at ambient temperature. All the tested reactions proceeded smoothly to furnish the corresponding α-hydroxyketones 3 in high yields, without the loss of enantiopurity (Figure 2). The enantiospecificity of the reaction (ee of 3/ee of 2) was more than 97% in all cases.
We propose two possible mechanisms for the nucleophilic substitution. The absolute configuration of 3b obtained from (S)-2b was determined to be R by comparison of its specific rotation with the reported value [26]. Therefore, it is assumed that the reaction proceeded in the usual SN2 fashion (Scheme 2, path a). However, an alternative reaction mechanism involving the formation of an epoxide intermediate is proposed, where the hydroxide ion attacks the carbonyl carbon to form epoxide intermediate 5 via the release of a chlorine atom with inversion of stereochemistry. The subsequent regeneration of a carbonyl group affords 3 (path b) [27].
In summary, we achieved the asymmetric synthesis of α-hydroxyketones by the organocatalytic enantioselective decarboxylative chlorination of β-ketocarboxylic acids and subsequent nucleophilic substitution with TBAOH. Our method would be a good alternative to the direct α-hydroxylation of simple ketones. An advantage of our method is that the safe and easy-to-handle reagent NCS is employed as the formal oxidant.

3. Materials and Methods

3.1. General Methods

All non-aqueous reactions were carried out in dried glassware under an argon atmosphere and stirred using magnetic stir-plates. Thin-layer chromatography analyses were performed using pre-coated silica gel plates with a fluorescent indicator (F254) (Merck Millipore, Darmstadt, Germany). Visualization was accomplished by ultraviolet (UV) light (254 nm), phosphomolybdic acid, or p-anisaldehyde. Flash column chromatography was performed using silica gel 60 (mesh size 40–100) (Kanto Chemical Co., Inc., Tokyo, Japan). 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a JNM-ECS400 (400 MHz 1H, 100 MHz 13C) or a JNM-ECX500 (500 MHz 1H, 126 MHz 13C) instrument (JEOL Ltd., Tokyo, Japan). Chemical shift values (δ) are reported in ppm (tetramethylsilane δ 0.00 ppm for 1H; residual chloroform δ 77.0 ppm for 13C). Direct analyses in real time (DART) mass (positive mode) analyses were performed on a JMS-T100TD time-of-flight mass spectrometer (JEOL Ltd.). Optical rotations were measured on a P-1030 digital polarimeter (JASCO Co., Ltd., Tokyo, Japan). Analytical high-performance liquid chromatography (HPLC) was performed on a PU1586 instrument with a MD-2018 plus diode array detector or PU1586 with a UV-1575 UV/Vis detector (JASCO Co., Ltd.) using a chiral column under the conditions described below. The enantiomeric purity of the compounds was determined by HPLC analyses using chiral stationary phase columns. 1H and 13C NMR spectra of compounds 1e, 2e and 3 and HPLC data of compounds 3 are available in Supplementary Materials.

3.2. Materials

Commercial grade reagents and solvents were used without further purification unless otherwise noted. Anhydrous toluene and tetrahydrofuran (THF) were purchased from Kanto Chemical Co., Inc. and used after purification by a Glass Contour solvent dispensing system (Pure Process Technology, Nashua, NH, USA). β-ketocarboxylic acids 1 and α-chloroketones 2 were prepared by the reported procedure [16].

3.3. Synthesis of β-ketocarboxylic Acid 1e

3.3.1. Tert-Butyl 2-(2-cyanobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate

tert-Butyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (2.6 mmol) in THF (2.1 mL) was added to a stirred suspension of NaH (60% in oil, washed by hexane) (5.2 mmol, 2.0 equiv.) in THF (5.0 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Then, 5-Iodopentanenitrile (5.2 mmol, 2.0 equiv.) in THF (2.1 mL) was added to the mixture, and the mixture was stirred under reflux for 9 h. The reaction was quenched by adding sat. NH4Cl aq. at 0 °C, and then extracted with ethyl acetate. The organic layer was washed by brine, dried over Na2SO4, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (hexane:ethyl acetate = 3:1) to yield the title compound as a yellowish oil (53% yield).
1H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 7.6 Hz, 1H), 7.46 (dd, J = 7.6, 7.6 Hz, 1H), 7.31 (dd, J = 7.6 Hz, 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 3.12–3.06 (m, 1H), 2.92 (dt, J = 17.2, 4.6 Hz, 1H), 2.49 (dt, J = 13.4, 4.6 Hz, 1H), 2.38 (t, J = 7.3 Hz, 2H), 2.14–2.08 (m, 1H), 1.92–1.86 (m, 2H), 1.75–1.63 (m, 3H), 1.51–1.44 (m, 1H), 1.33 (s, 9H); 13C NMR (126 MHz, CDCl3): 195.8, 171.0, 142.6, 133.2, 132.5, 128.6, 127.6, 126.6, 119.6, 82.2, 57.6, 33.2, 31.2, 27.7, 26.0, 25.8, 23.9, 16.9; HRMS (DART): [M + NH4]+ calcd. for C20H29N2O3, 345.21782; found, 345.21778.

3.3.2. 2-(4-Cyanobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1e)

Trifluoroacetic acid (16.8 mmol, 20 equiv.) was added to a stirred solution of tert-butyl 2-(2-cyanobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (0.84 mmol) in dichloromethane (4.2 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and then purified by flash column chromatography (hexane:diethyl ether = 4:1 to 1:2) to provide the title compound as a white solid (90% yield).
1H NMR (400 MHz, CDCl3): δ 8.06 (dd, J = 7.6 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.34 (t, J = 7.6Hz, 1H), 7.27–7.25 (m, 1H), 3.14–2.96 (m, 2H), 2.55–2.48 (m, 1H), 2.41–2.21 (m, 3H), 1.97–1.93 (m, 2H), 1.74–1.65 (m, 2H), 1.61–1.52 (m, 2H); 13C NMR (126 MHz, CDCl3): 196.9, 175.8, 143.3, 134.3, 131.0, 128.9, 128.3, 127.0, 119.4, 56.4, 33.1, 29.8, 25.5, 25.4, 23.9, 16.9; HRMS (DART): [M + NH4]+ calcd. for C16H21 N2O3, 289.15522; found, 289.15522.

3.4. Synthesis of α-chloroketone 2e

5-(2-Chloro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)pentanenitrile (2e)

N-chlorosuccinimide (0.74 mmol, 1.5 equiv.) and 2-(4-cyanobutyl)-1-oxo-1,2,3,4-tetrahydro naphthalene-2-carboxylic acid (0.50 mmol) was added to a stirred solution of amine catalyst C1 (0.05 mmol, 10 mol%) in toluene (25 mL) and the reaction mixture was stirred at 15 °C for 1 h. The crude product was purified by flash column chromatography (hexane:ethyl acetate = 3:1) to provide 2e as a pale yellow solid (86% yield, 98% ee).
1H NMR (500 MHz, CDCl3): δ 8.09 (d, J = 7.6 Hz, 1H), 7.53–7.50 (m, 1H), 7.36–7.33 (m, 1H), 7.26 (d, J = 7.6 Hz, 1H), 3.37–3.31 (m, 1H), 2.94–2.90 (m, 1H), 2.48–2.21 (m, 5H), 2.15–2.10 (m, 1H), 1.78–1.68 (m, 3H), 1.59–1.54 (m, 1H); 13C NMR (126 MHz, CDCl3): 190.8, 142.7, 133.8, 129.7, 128.7, 128.6, 126.9, 119.3, 70.6, 37.3, 34.9, 25.6, 25.3, 23.3, 16.9; HRMS (DART): [M + H]+ calcd. for C15H17Cl1N1O1, 262.09987; found, 262.09992.
The enantiomeric purity of 2e was determined by HPLC analysis (DAICEL CHIRALPAK IE-3 (0.46 cmϕ × 25 cm), hexane:2-propanol = 10:1, flow rate = 1.0 mL/min, retention time; 32.1 min (major) and 38.8 min (minor)).

3.5. Synthesis of α-hydroxyketones 3

3.5.1. 2-Allyl-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one (3a)

Tetrabutylammonium hydroxide (40% in water) (0.50 mmol, 1.5 equiv.) was added to a stirred solution of 2a (0.33 mmol) in acetonitrile (1.7 mL), and the mixture was stirred at room temperature for 5 h. The reaction mixture was directly purified by flash column chromatography (hexane:ethyl acetate = 8:1) to provide 3a as a pale yellow oil (68% yield, 95.9% ee) [13].
1H NMR (500 MHz, CDCl3): δ 8.02 (d, J = 7.6 Hz, 1H), 7.53 (dd, J = 7.6, 7.6 Hz, 1H), 7.35 (dd, J = 7.6, 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 5.92–5.84 (m, 1H), 5.17 (d, J = 10.3 Hz, 1H), 5.09 (dd, J = 17.0, 1.5 Hz, 1H), 3.83 (s, 1H), 3.14–3.07 (m, 1H), 2.99 (ddd, J = 18.0, 5.4, 2.3 Hz, 1H), 2.44 (dd, J = 14.1, 8.0 Hz, 1H), 2.38–2.33 (m, 2H), 2.17 (ddd, J = 13.0, 13.0, 5.4 Hz, 1H); 13C NMR (126 MHz, CDCl3): 201.0, 143.4, 134.1, 132.1, 130.1, 129.0, 128.0, 126.9, 119.1, 75.3, 40.3, 33.4, 26.1; HRMS (DART): [M + H]+ calcd. for C13H15O2, 203.10720; found, 203.10723.
[α]D19 + 3.94 (c = 1.35, CHCl3); The enantiomeric purity of 3a was determined by HPLC analysis (DAICEL CHIRALPAK IC-3 (0.46 cmϕ × 25 cm), hexane:2-propanol = 9:1, flow rate = 1.0 mL/min, retention time; 9.4 min (minor) and 10.8 min (major)).

3.5.2. (R)-2-Hydroxy-2-methyl-3,4-dihydronaphthalen-1(2H)-one (3b)

Tetrabutylammonium hydroxide (40% in water) (0.79 mmol, 1.5 equiv.) was added to a stirred solution of 2b (0.53 mmol) in acetonitrile (2.7 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 24 h. The mixture was quenched by adding sat. NH4Cl aq. and extracted with ethyl acetate. The organic layer was washed by brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane:ethyl acetate = 9:1 to 4:1) to provide 3b as a reddish oil (91% yield, 95.3% ee) [13].
1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 7.6 Hz, 1H), 7.53 (dd, J = 7.6, 7.6 Hz, 1H), 7.35 (dd, J = 7.6, 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 3.85 (s, 1H), 3.16–3.00 (m, 2H), 2.30–2.18 (m, 2H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 201.8, 143.4, 134.1, 129.9, 129.0, 128.0, 126.9, 73.6, 35.8, 26.8, 23.9; HRMS (DART): [M + H]+ calcd. for C11H13O2, 177.09155; found 177.09165.
[α]D26 + 12.5 (c = 0.75, CHCl3); The absolute of 3b was assigned by comparing its specific rotation with that of the same compound reported in the literature [26]. Lit. [α]D20 + 17.3 (c = 2.00, CHCl3) for 95% ee (R-configuration). The enantiomeric purity of 3b was determined by HPLC analysis (DAICEL CHIRALPAK IA-3 (0.46 cmϕ × 25 cm), hexane:2-propanol = 24:1, flow rate = 0.7 mL/min, retention time; 17.7 min (major) and 19.6 min (minor)).

3.5.3. 2-Benzyl-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one (3c)

Tetrabutylammonium hydroxide (40% in water) (0.34 mmol, 1.5 equiv.) was added to a stirred solution of 2c (0.22 mmol) in acetonitrile (1.1 mL), and the reaction mixture was stirred at room temperature for 7 h. The mixture was quenched by adding sat. NH4Cl aq. and extracted with ethyl acetate. The organic layer was washed by brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane:ethyl acetate = 8:1) to provide 3c as a yellow solid (56% yield, 92.6% ee) [13].
1H NMR (400 MHz, CDCl3): δ 8.03–8.01 (m, 1H), 7.57 (dd, J = 7.6, 7.6 Hz, 1H), 7.39 (dd, J = 7.6, 7.6 Hz, 1H), 7.32–7.24 (m, 4H), 7.16–7.14 (m, 2H), 3.78 (s, 1H), 3.27 (ddd, J = 18.0, 12.5, 5.5 Hz, 1H), 3.07–3.01 (m, 1H), 3.00 (d, J = 13.7 Hz, 1H), 2.92 (d, J = 13.7 Hz, 1H), 2.28 (ddd, J = 13.4, 5.5, 2.1 Hz, 1H), 2.20 (m, 1H); 13C NMR (100 MHz, CDCl3): 201.0, 143.2, 135.3, 134.1, 130.3, 129.1, 128.1, 128.0, 127.1, 126.9, 76.0, 41.9, 33.8, 26.3; HRMS (DART): [M + H]+ calcd. for C17H17O2, 253.12285; found, 253.12289.
[α]D26 – 23.5 (c = 1.47, CHCl3); The enantiomeric purity of 3c was determined by HPLC analysis (DAICEL CHIRALPAK IC-3 (0.46 cmϕ × 25 cm), hexane:2-propanol = 49:1, flow rate = 1.0 mL/min, retention time; 26.0 min (minor) and 29.2 min (major)).

3.5.4. 3-(2-Hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanenitrile (3d)

Tetrabutylammonium hydroxide (40% in water) (0.24 mmol, 1.5 equiv.) was added to a stirred solution of 2d (0.16 mmol) in acetonitrile (0.79 mL), and the reaction mixture was stirred at room temperature for 7 h. The reaction mixture was directly purified by open column chromatography (hexane:ethyl acetate = 3:1 to 1:1) to provide 3d as a colorless solid (43% yield, 94.6% ee).
1H NMR (500 MHz, CDCl3): δ 8.02 (d, J = 7.6 Hz, 1H), 7.58 (dd, J = 7.6, 7.6 Hz, 1H), 7.38 (dd, J = 7.6, 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 3.94 (s, 1H), 3.17–3.04 (m, 2H), 2.58 (ddd, J = 16.8, 9.6, 6.5 Hz, 1H), 2.39–2.31 (m, 2H), 2.22 (ddd, J = 13.8, 12.6, 6.1 Hz, 1H), 2.12 (ddd, J = 14.1, 9.6, 6.1 Hz, 1H), 1.99 (ddd, J = 14.1, 9.6, 5.7 Hz, 1H); 13C NMR (126 MHz, CDCl3): 200.4, 143.0, 134.7, 129.5, 129.2, 128.2, 127.3, 119.4, 74.3, 33.8, 31.2, 26.2, 11.4; HRMS (DART): [M + H]+ calcd. for C13H14 N1O2, 216.10245; found, 216.10247.
[α]D19 + 35.5 (c = 0.57, CHCl3); The enantiomeric purity of 3d was determined by HPLC analysis (DAICEL CHIRALPAK IB-3 (0.46 cmϕ × 25 cm), hexane:2-propanol = 10:1, flow rate = 1.0 mL/min, retention time; 18.3 min (major) and 21.0 min (minor)).

3.5.5. 5-(2-Hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)pentanenitrile (3e)

Tetrabutylammonium hydroxide (40% in water) (0.30 mmol, 1.5 equiv.) was added to a stirred solution of 2e (0.20 mmol) in acetonitrile (1.0 mL), and the reaction mixture was stirred at room temperature for 9 h. The reaction mixture was directly purified by open column chromatography (hexane:ethyl acetate = 3:1) to provide 3e as a yellow oil (74% yield, 96.0% ee).
1H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 7.6 Hz, 1H), 7.54 (dd, J = 7.6, 7.6 Hz, 1H), 7.36 (dd, J = 7.6, 7.6, 1H), 7.28–7.26 (m, 1H), 3.88 (s, 1H), 3.12–2.99 (m, 2H), 2.37–2.31(m, 3H), 2.17 (ddd, J = 13.4, 12.6, 6.1 Hz, 1H), 1.77–1.72 (m, 1H), 1.68–1.57 (m, 4H), 1.51–1.43 (m, 1H); 13C NMR (126 MHz, CDCl3): 201.6, 143.3, 134.2, 130.0, 129.1, 128.0, 127.0, 119.4, 75.3, 34.6, 33.8, 26.5, 25.5, 22.3, 17.1; HRMS (DART): [M + NH4]+ calcd. for C15H21N2O2, 261.16030; found, 261.16036.
[α]D19 + 37.9 (c = 1.18, CHCl3); The enantiomeric purity of 3e was determined by HPLC analysis (DAICEL CHIRALPAK IA-3 (0.46 cmϕ × 25 cm), hexane:2-propanol = 10:1, flow rate = 1.0 mL/min, retention time; 22.7 min (major) and 25.4 min (minor)).

3.5.6. 6-Chloro-3-hydroxy-3-methylchroman-4-one (3f)

Tetrabutylammonium hydroxide (40% in water) (0.21 mmol, 1.5 equiv.) was added to a stirred solution of 2f (0.14 mmol) in acetonitrile (0.68 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by open column chromatography (hexane:ethyl acetate = 5:1 to 1:1) to provide 3f as a colorless oil (39% yield, 91.8% ee).
1H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 2.7 Hz, 1H), 7.47 (dd, J = 8.8, 2.7 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.31, (d, J = 11.3 Hz, 1H), 4.20 (d, J = 11.3 Hz, 1H), 3.53 (s, 1H), 1.46 (s, 3H); 13C NMR (126 MHz, CDCl3): 195.5, 159.8, 136.5, 127.5, 126.8, 119.7, 119.0, 74.7, 70.6, 22.4; HRMS (DART): [M + H]+ calcd. for C10H10Cl1O3, 213.03185; found, 213.03190.
[α]D20 + 46.1 (c = 0.20, CHCl3); The enantiomeric purity of 3f was determined by HPLC analysis (DAICEL CHIRALPAK AD-H (0.46 cmϕ × 25 cm), hexane:2-propanol = 49:1, flow rate = 1.0 mL/min, retention time; 23.4 min (major) and 30.6 min (minor)).

3.5.7. 2-Hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (3g)

Tetrabutylammonium hydroxide (40% in water) (0.79 mmol, 3.0 equiv.) was added to a stirred solution of 2g (0.26 mmol) in acetonitrile (1.3 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 18 h. The reaction mixture was directly purified by open column chromatography (hexane:ethyl acetate = 2:1) to provide 3g as a colorless oil (77% yield, 88.7% ee) [13].
1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 7.6 Hz, 1H), 7.64 (dd, J = 7.6, 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.41 (dd, J = 7.6, 7.6 Hz, 1H), 3.28 (d, J = 16.8 Hz, 1H), 3.23 (d, J = 16.8 Hz, 1H), 2.81 (br, 1H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 208.0, 151.2, 135.9, 133.5, 127.9, 126.8, 124.9, 77.4, 42.1, 25.7; HRMS (DART): [M + H]+ calcd. for C10H11O2, 163.07590; found, 163.07592.
[α]D20 + 38.8 (c = 1.1, CHCl3); The enantiomeric purity of 3g was determined by HPLC analysis (DAICEL CHIRALPAK IC-3 (0.46 cmϕ × 25 cm), hexane:2-propanol = 9:1, flow rate = 0.7 mL/min, retention time; 22.6 min (minor) and 24.2 min (major)).

3.5.8. 2-Benyl-2-hydroxycyclohexan-1-one (3h)

Tetrabutylammonium hydroxide (40% in water) (0.12 mmol, 1.5 equiv.) was added to a stirred solution of 2h (0.082 mmol) in acetonitrile (0.41 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by open column chromatography (hexane:ethyl acetate = 5:1) to provide 3h as a colorless solid (79% yield, 39.7% ee) [28].
1H NMR (500 MHz, CDCl3): δ 7.29–7.19 (m, 5H), 3.86 (s, 1H), 3.14 (d, J = 13.8 Hz, 1H), 2.98 (d, J = 13.8 Hz, 1H), 2.70 (ddd, J = 14.1, 13.8, 6.1 Hz, 1H), 2.56–2.52 (m, 1H), 2.24–2.15 (m, 2H), 1.95–1.84 (m, 2H), 1.74–1.63 (m, 2H); 13C NMR (126 MHz, CDCl3): 213.2, 135.3, 130.0, 128.2, 126.9, 79.2, 43.2, 40.3, 38.5, 27.9, 22.8; HRMS (DART): [M + NH4]+ calcd. for C13H20N1O2, 222.14940; found, 222.14940.
[α]D20 – 33.3 (c = 0.58, CHCl3); The enantiomeric purity of 3h was determined by HPLC analysis (DAICEL CHIRALPAK OJ-H (0.46 cmϕ × 25 cm), hexane:2-propanol = 10:1, flow rate = 1.0 mL/min, retention time; 17.4 min (minor) and 19.6 min (major)).

Supplementary Materials

The following are available online: 1H and 13C NMR spectra of compounds 1e, 2e and 3 and HPLC data of compounds 3.

Author Contributions

K.S. conceived and designed the project; M.K.K., A.S. and R.K. performed the experiments and analyzed the data while discussing with K.S.; K.S. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Grants-in-Aid for Scientific Research (B) (18H01974) from JSPS and the Toyota RIKEN Scholar Program from the Toyota Physical and Chemical Research Institute.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
Molecules 25 03902 sch001 550
Scheme 1. Asymmetric construction of a tetrasubstituted stereogenic center by enantioselective decarboxylative chlorination and subsequent nucleophilic substitution.
Scheme 1. Asymmetric construction of a tetrasubstituted stereogenic center by enantioselective decarboxylative chlorination and subsequent nucleophilic substitution.
Molecules 25 03902 sch001
Molecules 25 03902 g001 550
Figure 1. Synthesis of optically active α-chloroketones 2 [a] ([a] Reactions were carried out with 10 mol% C1 and 1.5 equiv. of NCS at ambient temperature in toluene (0.2 M), unless otherwise noted. [b] Reaction was carried out for 2 days at –20 °C).
Figure 1. Synthesis of optically active α-chloroketones 2 [a] ([a] Reactions were carried out with 10 mol% C1 and 1.5 equiv. of NCS at ambient temperature in toluene (0.2 M), unless otherwise noted. [b] Reaction was carried out for 2 days at –20 °C).
Molecules 25 03902 g001
Molecules 25 03902 g002 550
Figure 2. Substrate scope [a] ([a] Reactions were carried out with 1.5 equiv. of TBAOH at ambient temperature in acetnitrile, unless otherwise noted. [b] Reaction was carried out at 0 °C. [c] Reaction was carried out with 3.0 equiv. of TBAOH at 0 °C. es: enantiospecificity).
Figure 2. Substrate scope [a] ([a] Reactions were carried out with 1.5 equiv. of TBAOH at ambient temperature in acetnitrile, unless otherwise noted. [b] Reaction was carried out at 0 °C. [c] Reaction was carried out with 3.0 equiv. of TBAOH at 0 °C. es: enantiospecificity).
Molecules 25 03902 g002
Molecules 25 03902 sch002 550
Scheme 2. Two possible reaction pathways.
Scheme 2. Two possible reaction pathways.
Molecules 25 03902 sch002
Table
Table 1. Optimization of reaction conditions [a].
Table 1. Optimization of reaction conditions [a].
Molecules 25 03902 i001
EntryNucleophileSolventTime (h)Conv. (%) [b] of rac-2aYield (%) [c] of rac-3aYield (%) [c] of 4a
1NaOH aq. (10 M)CH3CN51911
2KOH aq. (10 M)CH3CN51043
3TBAF·nH2O (1.0 M in THF)CH3CN561138
4TBAOH (40% in water)CH3CN5996814
5TBAOH (40% in water)THF4965933
6TBAOH (40% in water)DMPU45 min1004839
7TBAOH (40% in water)DMF21005227
8TBAOH (40% in water)toluene433225
[a] Reactions were carried out with 1.5 equiv. of nucleophile at ambient temperature. [b] Calculated based on the number of moles of recovered 2a. [c] Isolated yield. DMPU: N,N′-dimethylpropyleneurea.

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Kam, M.K.; Sugiyama, A.; Kawanishi, R.; Shibatomi, K. Asymmetric Synthesis of Tertiary α -Hydroxyketones by Enantioselective Decarboxylative Chlorination and Subsequent Nucleophilic Substitution. Molecules 2020, 25, 3902. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25173902

AMA Style

Kam MK, Sugiyama A, Kawanishi R, Shibatomi K. Asymmetric Synthesis of Tertiary α -Hydroxyketones by Enantioselective Decarboxylative Chlorination and Subsequent Nucleophilic Substitution. Molecules. 2020; 25(17):3902. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25173902

Chicago/Turabian Style

Kam, Mei Kee, Akira Sugiyama, Ryouta Kawanishi, and Kazutaka Shibatomi. 2020. "Asymmetric Synthesis of Tertiary α -Hydroxyketones by Enantioselective Decarboxylative Chlorination and Subsequent Nucleophilic Substitution" Molecules 25, no. 17: 3902. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25173902

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