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Article

Asymmetric Electrophilic Difluoromethylthiolation of Indanone-Based β-Keto Esters Using Difluoromethanesulfonyl Hypervalent Iodonium Ylides

by
Satoshi Gondo
1,
Okiya Matsubara
1,
Hélène Chachignon
2,
Yuji Sumii
1,
Dominique Cahard
2 and
Norio Shibata
1,3,*
1
Department of Nanopharmaceutical Sciences, Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
2
CNRS, UMR 6014 COBRA, Normandie Université, 1 Rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France
3
Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, Jinhua 321004, China
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(2), 221; https://doi.org/10.3390/molecules24020221
Submission received: 8 December 2018 / Revised: 29 December 2018 / Accepted: 3 January 2019 / Published: 9 January 2019
(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)
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Abstract

:
The first electrophilic diastereoselective direct introduction of the difluoromethylthio group is described. We used a chiral auxiliary-based approach to illustrate the versatility of our recently developed difluoromethanesulfonyl hypervalent iodonium ylide reagents for the difluoromethylthiolation of indanone-based β-keto esters. Chiral SCF2H-featuring compounds were obtained in up to 93% ee value.

Graphical Abstract

1. Introduction

In the field of organofluorine chemistry one of the major present concerns is the development of new methods for the construction of novel chemical scaffolds. In this vein, the combination of sulfur, carbon and fluorine atoms has given birth to emergent motifs, which include SCF3, SCF2H, SCF2FG (FG = SO2Ar, SAr, PO(OR)2, COAr, Rf), SCFH2 [1,2,3,4]. The most recurring motif is undoubtedly the SCF3 one, which use grew at an unprecedented rate in the past recent years. The SCF3 chemotype is encountered in several biologically active molecules, albeit virtually absent in marketed drugs. The reason it elicits such enthusiasm is the exceptional high lipophilicity of SCF3 molecules that confers a high potential in medicinal chemistry. Equally interesting, though less often investigated, is the SCF2H group that also possess high lipophilicity while acting as hydrogen-bond donor owing to the acidity of the hydrogen atom [5]. The synthesis of enantioenriched molecules featuring a SCF2R motif directly linked to the chiral center is an issue worth consideration in the context of designing new chiral drugs. Asymmetric synthesis of trifluoromethylthiolated compounds have been investigated [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22], and very recently Shibata and co-workers published the asymmetric synthesis of α-tri- and difluoromethylthio allyl ketones via electrophilic difluoromethylthiolation of β-keto esters using difluoromethanesulfonyl hypervalent iodonium ylide 1a followed by a Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation (DAAA, Scheme 1a) [23]. However, there is no report describing the asymmetric synthesis of difluoromethylthio compounds via a direct difluoro- methylthiolation reaction. Hence, we have been interested in direct asymmetric electrophilic difluoromethylthiolations. For this purpose, we targeted SCF2H analogues of α-hydroxy β-keto esters, in particular those with an indanone scaffold [24,25,26] that are ubiquitous and important structural motifs, as such or in a masked form, in a wide range of biologically active natural products and synthetic pharmaceuticals and agrochemicals [27,28,29,30,31,32,33,34]. Moreover, we decided to valorize our difluoromethanesulfonyl hypervalent iodonium ylides 1a,b as electrophilic difluoromethyl- thiolation reagents for a wide range of nucleophiles [24]. Herein, we report the first asymmetric electrophilic introduction of the difluoromethylthio group onto chiral enamines derived from β-keto esters (Scheme 1b).

2. Results and Discussion

We recently demonstrated that the difluoromethylthiolation of enamines obtained from β-keto esters was efficient and had wide generality [24], thus we surmised that the enamine approach would nicely extend to chiral enamines. In a first series of experiments, we studied the difluoro- methylthiolation of β-enamino esters 2a–e prepared from methyl 6-methyl-1-indanone-2- carboxylate and various chiral amines in order to determine the most appropriate chiral auxiliary (Table 1). The optimized reaction conditions found for the difluoromethylthiolation of achiral β-enamino esters were first applied to chiral β-enamino esters 2a–e. In the presence of 20 mol% of copper bromide, the difluoromethanesulfonyl hypervalent iodonium ylide 1b reacted in 1,4-dioxane at room temperature for 5 h followed by acidic cleavage of the resulting imine product to afford the 2-difluoromethylthio-1,3-dicarbonyl compound 3. The (S)-(–)-α-methylbenzylamine auxiliary gave the desired product 3 in good yield and an encouraging 57% ee value (Table 1, entry 1). Variations of the Ar and R groups of the chiral amine indicated that the bulkier (S)-(–)-1-(1-naphthyl)ethylamine led to enhanced enantioselectivity (Table 1, entry 3) albeit in a lower chemical yield.
Next, we conducted a second series of experiments in order to optimize the reaction solvent with substrates 2a or 2c. Solvent screening revealed an increase in enantioselectivity in going from ether-containing solvents (1,4-dioxane, THF), chlorinated solvents (CH2Cl2, CHCl3) to aromatic toluene, which provided the highest ee values of 69 and 88% ee, respectively, for both phenyl and naphthyl-based auxiliaries (Table 2). A survey of other parameters that are the amount and the nature (1a versus 1b) of the difluoromethanesulfenylating reagent and the amount and nature of the copper catalyst was also performed but deviation from standard conditions did not allow to improve the reactivity nor the enantioselectivity. We further attempted the reaction of β-keto esters with 1b in the presence of a catalytic amount of chiral amine, (R)-1-(naphthalen-1-yl)ethan-1-amine, but the reaction did not proceed well giving 3a in a low yield (<10%).
Having identified the suitable chiral auxiliary and the reaction conditions, we then turned our efforts to exploring other indanone-based enamine substrates featuring various substituents on the aromatic ring (Scheme 2).
We noticed that the enantiomeric excess increased for electron-donating substituents (MeO > Me > H) with a cumulative effect (two MeO > MeO, products 3a–d). Halogen substituted indanone-based enamines were compatible with the reaction conditions and gave similar ee values to the undecorated indanone (3e,f versus 3b). The size of ester does not much affect the yield and enantioselectivity on the transformation (3b, R2 = Me and 3g, R2 = Et, Scheme 2). In addition to these indanone carboxylates, we also attempted the substrates having six-membered tetralone-type structure and acyclic substrates. However, the tetralone-type substrate failed to deliver the corresponding β-enamino ester and an acyclic β-enamino ester produced a SCF2H-product 3h with a low ee (12%, see Scheme 2). The chiral amine auxiliary was recovered in 25% yield after the reaction with 2d (not optimized) [36].
With regard to the reaction mechanism based on our previous reports [24,37], we proposed a copper-catalyzed generation of carbene A by reaction of the difluoromethanesulfonyl hypervalent iodonium ylide 1b followed by formation of the oxathiirene-2-oxide B, which rearranged to the sulfoxide C and collapsed into the thioperoxoate D. This SCF2H thioperoxoate was supposed to be the active electrophilic HF2CS+ donor that reacted with the β-enamino esters 2. The resulting iminium was then hydrolyzed under acidic conditions to release the desired α-SCF2H β-keto esters 3 (Scheme 3).

3. Materials and Methods

3.1. General Information

All reagents were used as received from commercial sources, unless specified otherwise. Enamino esters were prepared referring to previously reported procedures [37,38,39]. Reactions requiring anhydrous conditions were performed in flame-dried glassware under a positive pressure of nitrogen. Reaction mixtures were stirred magnetically. Solvents were transferred via syringe and were introduced into the reaction vessels though a rubber septum. All of the reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica-gel (60-F254) (Merck, Kenilworth, NJ, USA). The TLC plates were visualized with UV light and 7% phosphomolybdic acid or KMnO4 in water/heat. Preparative thin-layer plates carried out on 2.0 mm Merck silica gel (60-F254). Column chromatography was carried out on a column packed with silica-gel 60N spherical neutral size 50–63 μm. The 1H-NMR (300, 700 MHz) was recorded on a Varian Mercury 300 (Agilent Technologies, Palo Alto, CA, USA) or an ECZ-700R (JEOL Ltd, Tokyo, Japan) instrument, with TMS (δ = 0.00 ppm) as internal standard, and 19F-NMR (282 MHz) spectra was recorded on a Varian Mercury 300 with C6F6 (δ = −162.2 ppm) as internal standard. The 13C-NMR (125 MHz) spectra were recorded on an Avance 500 spectrometer (Bruker, Billerica, MA, USA). Chemical shifts (δ) are reported in parts per million and coupling constants (J) are in hertz. The following abbreviations were used to show the multiplicities: s: singlet, d: doublet, t: triplet, q: quadruplet, dd: doublet of doublets, td: triplet of doublets, dt: doublet of triplets, m: multiplet, br: broad. All the melting points are uncorrected. Mass spectra were recorded on an LCMS-2020EV (ESI-MS) system (Shimadzu Corporation, Kyoto, Japan). Infrared spectra were recorded on a FT/IR-4100 spectrometer (JASCO Corporation, Tokyo, Japan). HPLC analyses were performed on a JASCO PU-2080 Plus system using a 4.6 × 250 mm CHIRALPAK IB-3 column and a CHIRALCEL OD-3 column. Optical rotations were measured on a SEPA-300 instrument (HORIBA Ltd, Kyoto, Japan). High resolution mass spectrometry were recorded on a Synapt G2 HDMS (ESI-MS) system (Waters Corporation, Milford, MA, USA). The chiral amines: (S)-(−)-α-methylbenzylamine (≥99.5% ee), (S)-(−)-α-ethylbenzylamine (≥99.0% ee), (S)-(−)-4-methoxy- α-methylbenzylamine (≥97.5% ee) were purchased from Sigma Aldrich (St. Louis, MI, USA). (S)-(–)-1-(1-Naphthyl)ethylamine (>98.0% ee), and (S)-(−)-1-(p-tolyl)ethylamine were purchased from TCI (Tokyo, Japan). The 1H, 13C and 19F NMR spectra of compounds 3 and HPLC data of compounds 3 are available in the Supplementary Material.

3.2. Synthesis of Chiral Enamine (General Procedure)

Amine (2.2 mmol, 1.5 equiv) was added to a solution of β-ketoester (1.47 mmol) and zinc acetate (0.29 mmol, 20 mol%) in methanol under nitrogen atmosphere, the reaction mixture was refluxed for 16–64 h. After the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (with ethyl acetate: hexane mixtures as eluent).
Methyl 5-methyl-3-((1-phenylethyl)amino)-1H-indene-2-carboxylate (2a). Following the general procedure the reaction mixture was stirred at 50 °C for 53 h. After the reaction was complete, the mixture was worked up as described. Brown solid (35%, 156.6 mg). 1H-NMR (300 MHz, CDCl3) δ 8.29 (d, J = 6.3 Hz, 1H), 7.21–7.43 (m, 7H), 7.11 (d, J = 7.8 Hz, 1H), 5.36–5.41 (m, 1H), 3.81 (s, 3H), 3.50 (s, 2H), 2.27 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 21.5, 26.0, 33.9, 50.4, 53.8, 97.2, 124.3, 124.5, 125.4 (2C), 127.0, 128.7 (2C), 129.2, 135.6, 137.6, 142.6, 145.3, 159.1, 168.8. IR (KBr): 3284, 2958, 2924, 1643, 1587, 1564, 1444, 1317, 1267, 1205 cm−1. MS (ESI): m/z 308 (M + H)+.
Methyl 5-methyl-3-((1-phenylpropyl)amino)-1H-indene-2-carboxylate (2b). Gray solid (30%, 153.5 mg). 1H-NMR (300 MHz, CDCl3) δ 8.36 (d, J = 8.1 Hz, 1H), 7.19–7.40 (m, 7H), 7.10 (d, J = 7.8 Hz, 1H), 5.09–5.15 (m, 1H), 3.82 (s, 3H), 3.49 (s, 2H), 2.27 (s, 3H), 1.90–1.99 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 10.7, 21.5, 32.8, 33.9, 50.3, 59.8, 97.1, 124.3, 124.5, 126.0 (2C), 126.9, 128.6 (2C), 129.2, 135.5, 137.6, 142.6, 144.0, 159.6, 168.9. IR (KBr): 3273, 2970, 2951, 1651, 1595, 1568, 1460, 1309, 1263, 1194 cm−1. MS (ESI): m/z 322 (M + H)+.
Methyl 5-methyl-3-((1-(naphthalen-1-yl)ethyl)amino)-1H-indene-2-carboxylate (2c). Pale yellow solid (40%, 211.0 mg). 1H-NMR (300 MHz, CDCl3) δ 8.48 (d, J = 6.3 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.60–7.66 (m, 2H), 7.55–7.50 (m, 1H), δ 7.38 (t, J = 7.7 Hz, 1H), 7.20–7.24 (m, 1H), 7.10 (s, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.09–6.14 (m, 1H), 3.83 (s, 3H), 3.49 (d-like, 2H), 1.83 (s, 3H), 1.78 (d, J = 6.6 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 21.0, 24.8, 33.9, 50.1, 50.4, 96.8, 121.7, 122.6, 124.1, 124.3, 125.5, 125.9, 126.4, 127.6, 129.1, 129.2, 129.7, 133.8, 135.3, 137.4, 140.9, 142.4, 159.0, 168.9. IR (KBr): 3296, 3059, 2885, 2862, 1655, 1591, 1564, 1448, 1267, 1186 cm−1. MS (ESI): m/z 358 (M + H)+.
Methyl 5-methyl-3-((1-(p-tolyl)ethyl)amino)-1H-indene-2-carboxylate (2d). Yellow solid (20%, 96.6 mg). 1H-NMR (300 MHz, CDCl3) δ 8.26 (d, J = 6.9 Hz, 1H), 7.41 (s, 1H), 7.28–7.29 (m, 3H), 7.09–7.14 (m, 3H), 5.35 (t, J = 6.6 Hz, 1H), 3.80 (s, 3H), 3.48 (s, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 1.64 (d, J = 3.6 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 21.0, 21.6, 26.1, 33.9, 50.4, 53.5, 97.0, 124.4, 124.5, 125.3 (2C), 129.2, 129.4 (2C), 135.6, 136.5, 137.6, 142.3, 142.7, 159.2, 168.9. IR (KBr): 3307, 3032, 2924, 2316, 1651, 1595, 1556, 1448, 1263, 1201 cm−1. MS (ESI): m/z 322 (M + H)+.
Methyl 3-((1-(4-methoxyphenyl)ethyl)amino)-5-methyl-1H-indene-2-carboxylate (2e). Pale yellow solid (32%, 156.3 mg). 1H-NMR (300 MHz, CDCl3) δ 8.23 (d, J = 7.2 Hz, 1H), 7.40 (s, 1H), 7.25–7.34 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 5.31–5.36 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.48 (s, 2H), 2.28 (s, 3H), 1.63 (d, J = 6.3 Hz, 3H). 13C-NMR (125 MHz, CDCl3). IR (KBr): 3276, 2997, 2939, 2831, 1647, 1610, 1587, 1506, 1452, 1329, 1259, 1190, 1174, 1092 cm−1. MS (ESI): m/z 338 (M + H)+.
Methyl 3-((1-(naphthalen-1-yl)ethyl)amino)-1H-indene-2-carboxylate (2f). Yellow solid (42%, 214.1 mg). 1H-NMR (300 MHz, CDCl3) δ 8.47 (d, J = 6.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.52–7.67 (m, 3H), 7.37–7.42 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 6.07–6.17 (m, 1H), 3.84 (s, 3H), 3.56 (s, 2H), 1.79 (d, J = 6.6 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 24.9 34.3, 50.5, 96.7, 122.0, 122.5, 123.3, 124.9, 125.6, 125.9, 126.3, 126.5, 127.7, 128.2, 129.3, 129.8, 134.0, 137.3, 140.6, 145.5, 159.0, 169.0. IR (KBr): 3292, 3062, 2966, 2951, 1747, 1655, 1606, 1568, 1444, 1529, 1190 cm−1. MS (ESI): m/z 344 (M + H)+.
Methyl 5-methoxy-3-((1-(naphthalen-1-yl)ethyl)amino)-1H-indene-2-carboxylate (2g). Yellow solid (46%, 250.4 mg). 1H-NMR (300 MHz, CDCl3) δ 8.48 (d, J = 4.5 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.70–7.76 (m, 2H), 7.50–7.63 (m, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.73 (dd, J = 8.4, 2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.01–6.09 (m, 1H), 3.85 (s, 3H), 3.53 (d, J = 22.2 Hz, 1H), 3.44 (d, J = 22.2 Hz, 1H), 2.71 (s, 3H), 1.82 (d, J = 6.9 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 33.6, 50.5, 50.6, 54.3, 97.7, 106.6, 116.9, 121.9, 122.7, 125.2, 125.7, 126.2, 126.5, 127.6, 129.3, 129.6, 134.0, 137.6, 138.1, 141.0, 158.1, 159.1, 168.9. IR (KBr): 3300, 3057, 2945, 2829, 1741, 1655, 1614, 1576, 1452, 1225, 1132, 1086 cm−1. MS (ESI): m/z 374 (M + H)+.
Methyl 5,6-dimethoxy-3-((1-(naphthalen-1-yl)ethyl)amino)-1H-indene-2-carboxylate (2h). Yellow solid (45%, 265.6 mg). 1H-NMR (300 MHz, CDCl3) δ 8.54 (br s, 1H), δ 8.17 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.69–7.75 (m, 2H), 7.50–7.63 (m, 2H), 7.38–7.43 (m, 1H), 6.85 (s, 1H), 6.47 (s, 1H), 5.96–6.05 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.53 (d, J = 22.2 Hz, 1H), 3.44 (d, J = 22.2 Hz, 1H) 2.61 (s, 3H), 1.83 (d, J = 6.3 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 24.7, 34.1, 50.3, 50.5, 54.6, 55.8, 95.3, 106.0, 107.2, 121.8, 122.7, 125.7 126.2, 126.5, 127.6, 129.1, 129.4, 129.5, 133.9, 139.1, 140.9, 147.4, 149.8, 159.7, 168.6. IR (KBr): 3300, 2947, 1739, 1643, 1595, 1556, 1448, 1309, 1252, 1209 cm−1. MS (ESI): m/z 404 (M + H)+.
Methyl 6-bromo-3-((1-(naphthalen-1-yl)ethyl)amino)-1H-indene-2-carboxylate (2i). Yellow solid (42%, 262.9 mg). 1H-NMR (300 MHz, CDCl3) δ 8.41 (br d, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.50–7.65 (m, 4H), 7.39 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.00–6.05 (m, 1H), 3.84 (s, 3H), 3.53 (s, 2H), 1.78 (d, J = 6.6 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 24.8, 34.2, 50.4, 50.6, 96.9, 121.7, 122.5, 122.8, 124.3, 125.7, 125.9, 126.7, 127.8, 128.0, 123.0, 129.4, 129.6, 134.0, 136.3, 140.3, 147.3, 158.0, 168.7. IR (KBr): 3296, 3059, 2939, 2858, 1739, 1658, 1610, 1560, 1452, 1325, 1255, 1186 cm−1. MS (ESI): m/z 422 (M + H)+.
Methyl 6-fluoro-3-((1-(naphthalen-1-yl)ethyl)amino)-1H-indene-2-carboxylate (2j). Yellow solid (43%, 230.9 mg). 1H-NMR (300 MHz, CDCl3) δ 8.47 (d, J = 6.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.60–7.66 (m, 2H), 7.53–7.58 (m, 1H), 7.37–7.42 (m, 1H), 7.19 (dd, J = 8.7, 5.1 Hz, 1H), 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 6.59 (td, J = 9.0, 2.4 Hz, 1H), 6.00–6.09 (m, 1H), 3.84 (s, 3H), 3.59 (d, J = 22.8 Hz, 1H), 3.50 (d, J = 22.8 Hz, 1H) 1.78 (d, J = 6.6 Hz, 3H). 19F-NMR (282 MHz, CDCl3) δ −113.3 (s, 1F). 13C-NMR (125 MHz, CDCl3) δ 24.9, 34.4, 50.4, 50.5, 96.5, 112.1 (d, J = 22.5 Hz, 1C), 113.6 (d, J = 22.5 Hz, 1C), 121.8, 122.5,124.4 (d, J = 8.8 Hz, 1C), 125.7, 125.9, 126.7, 127.8, 129.4, 129.7, 133.4, 134.0, 140.4, 148.2 (d, J = 8.8 Hz, 1C), 158.2, 163.1 (d, J = 247.5 Hz, 1C), 168.8. IR (KBr): 3296, 3057, 2945, 1741, 1655, 1614, 1576, 1452, 1225, 1132, 1086 cm−1. MS (ESI): m/z 362 (M + H)+.
Ethyl 3-((1-(Naphthalen-1-Yl)ethyl)amino)-1H-Indene-2-Carboxylate (2k). Amine (2.0 mmol, 1.5 equiv) was added to a solution of β-ketoester (1.35 mmol) and zinc acetate (0.27 mmol, 20 mol%) in methanol under a nitrogen atmosphere, the reaction mixture was refluxed for 60 h. After reaction, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: hexane). Yellow solid (43%, 205.6 mg). 1H-NMR (300 MHz, CDCl3) δ 8.45 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.52–7.68 (m, 3H), 7.37–7.42 (m, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.08–6.16 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.61 (d, J = 22.8 Hz, 1H), 3.53 (d, J = 23.1 Hz, 1H), 1.78 (d, J = 6.9 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 14.8, 24.9, 34.4, 50.3, 58.9, 97.1, 122.0, 122.5, 123.8, 124.8, 125.5, 125.9, 126.2, 126.5, 127.6, 128.1, 129.2, 129.8, 133.9, 137.4, 140.6, 145.6, 158.7, 168.6. IR (KBr): 3296, 3059, 2974, 1739, 1647, 1610, 1591, 1564, 1441, 1259, 1186, 1120 cm−1. MS (ESI): m/z 358 (M + H)+.

3.3. Representative Procedure for the Diastereoselective Difluoromethylthiolation

General Procedure

Reagent 1b [24] (0.40 mmol, 2.0 equiv) was added to a solution of enamine (0.20 mmol, 1.0 equiv) and CuBr (0.04 mmol, 20 mol%) in toluene (2.5 mL) under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 5 h. HCl (1 M) was added to the reaction mixture which was then stirred for 12 h. After that, the mixture was extracted with ethyl acetate two times, then washed with brine and dried by Na2SO4. The ethyl acetate was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate: hexane) or (CH2Cl2: hexane).
Methyl 2-((difluoromethyl)thio)-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3a) [23,24,25]. Yellow oil (24.2 mg, 45%, 88% ee). The ee value was determined by HPLC analysis using a Chiralpack IB3 column (hexane/iPrOH = 98:2, flow rate: 0.5 mL/min, tR (minor) =18.8 min (integral = 5.9%), tR (major) = 21.8 min (integral = 94.1%). 1H-NMR (300 MHz, CDCl3) δ 7.64 (s, 1H), 7.52 (S, 1H), 7.50 (t, J = 55.7 Hz 1H), 7.36 (d, J = 7.6 Hz, 1H), 3.98 (d, J = 17.6 Hz, 1H), 3.81 (s, 3H), 3.22 (d, J = 17.9 Hz, 1H), 2.43 (s, 3H). 19F-NMR (282 MHz, CDCl3) δ −92.1 (dd, J = 251.7, 55.2 Hz, 1F), −93.5 (dd, J = 250.9, 56.0 Hz, 1F). HRMS (ESI) m/z Calcd: 309.0373 for C13H12O3F2SNa (M + Na)+ Found: 309.0370.
Methyl 2-((difluoromethyl)thio)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3b). Pale yellow solid (30.7 mg, 56%, 85% ee). [α]25D = + 6.6 (c = 0.77, CHCl3). The ee value was determined by HPLC analysis using a Chiralpack IB3 column (hexane/iPrOH = 98:2, flow rate: 0.5 mL/min, tR (minor) = 30.2 min (integral = 7.4%), tR (major) = 33.5 min (integral = 92.5%). 1H-NMR (700 MHz, CDCl3) δ 7.84 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 52.2 Hz, 1H), 7.47 (s, 3H), 7.44–7.50 (m, 2H), 4.04 (d, J = 17.9 Hz, 1H), 3.82 (s, 3H), 3.27 (d, J = 17.9 Hz, 1H). 19F-NMR (282 MHz, CDCl3) δ −92.0 (dd, J = 250.9, 56.0 Hz, 1F), −93.4 (dd, J = 250.0, 55.2 Hz, 1F). 13C-NMR (125 MHz, CDCl3) δ 196.9, 169.0, 150.7, 136.5, 133.1, 120.4 (t, J = 271.1 Hz), 122.6, 120.4, 118.3, 58.6, 54.2, 39.7. IR (KBr): 3032, 2966, 1759, 1720, 1603, 1464, 1433, 1248, 1190, 1068, 1030 cm−1. HRMS (ESI) m/z Calcd: 295.0216 for C12H10O3F2SNa (M + Na)+, Found 295.0228.
Methyl 2-((difluoromethyl)thio)-6-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3c) [24,26]. Yellow oil (31.1 mg, 51%, 90% ee). [α]25D = −15.7 (c = 0.64, CHCl3). The ee value was determined by HPLC analysis using a Chiralpack IB3 column (hexane/iPrOH = 95:5, flow rate: 0.5 mL/min, tR (minor) = 23.9 min (integral = 5.1%), tR (major) = 25.9 min (integral = 94.9%). 1H-NMR (300 MHz, CDCl3) δ 7.52 (t, J = 55.7 Hz, 1H), 7.25–7.38 (m, 3H), 3.95 (d, J = 17.6 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.20 (d, J = 17.6 Hz, 1H). 19F-NMR (282 MHz, CDCl3) δ −92.1 (dd, J = 251.7, 55.2 Hz, 1F), −93.5 (dd, J = 250.9, 56.0 Hz, 1F). HRMS (ESI) m/z Calcd: 325.0322 for C13H12O4F2NaS (M + Na)+ Found: 325.0325.
Methyl 2-((difluoromethyl)thio)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3d) [26]. Brown solid (36.2 mg, 54%, 94% ee). [α]25D = −12.3 (c = 0.70, CHCl3). The ee value was determined by HPLC analysis using a Chiralpack OD-3 column (hexane/iPrOH = 95:5, flow rate: 1.0 mL/min, tR (minor) = 27.2 min (integral = 3.2%), tR (major) = 29.3 min (integral = 96.8%). 1H-NMR (300 MHz, CDCl3) δ 7.52 (t, J = 55.7 Hz, 1H), 7.27 (s, 1H), 6.88 (s, 1H), 4.00 (s, 3H), 3.93 (m, 4H), 3.82 (s, 3H), 3.21 (d, J = 17.6 Hz, 1H). 19F-NMR (282 MHz, CDCl3) δ −91.9 (dd, J = 250.9, 56.0 Hz, 1F), −93.5 (dd, J = 250.9, 56.0 Hz, 1F). HRMS (ESI) m/z Calcd: 355.0428 for C14H14O5F2SNa (M + Na)+ Found: 355.0427.
Methyl 5-bromo-2-((difluoromethyl)thio)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3e). Brown solid (22.6 mg, 32%, 88% ee). M.p. 58.2–63.8 °C. [α]25D = −2.5 (c = 1.1, CHCl3). The ee value was determined by HPLC analysis using a Chiralpack OD-3 column (hexane/iPrOH = 95:5, flow rate: 1.0 mL/min, tR (minor) = 10.6 min (integral = 5.9%), tR (major) = 12.0 min (integral = 94.0%). 1H-NMR (300 MHz, CDCl3) δ 7.72–7.63 (m, 3H), 7.45 (t, J = 53.3 Hz, 1H), 4.03 (d, J = 18.5 Hz, 1H), 3.83 (s, 3H), 3.27 (d, J = 17.9 Hz, 1H). 19F-NMR (282 MHz, CDCl3) δ −91.9 (dd, J = 250.9, 56.0 Hz, 1F), −93.5 (dd, J = 250.0, 55.2 Hz, 1F). 13C-NMR (125 MHz, CDCl3) δ 195.7, 168.5, 152.2, 132.5, 132.2, 132.0, 129.8, 127.1, 120.3 (t, J = 271.6 Hz), 58.768, 54.4, 39.3. IR (KBr): 2958, 1747, 1709, 1591, 1425, 1317, 1259, 1209, 1057, 1030 cm−1. HRMS (ESI) m/z Calcd: 372.9322 for C12H9O3F2NaSBr (M + Na)+ Found: 372.9309.
Methyl 2-((difluoromethyl)thio)-5-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3f). Yellow oil (36.5 mg, 63%, 86% ee). [α]25D = + 6.5 (c = 0.77, CHCl3). The ee value was determined by HPLC analysis using a Chiralpack OD-3 column (hexane/iPrOH = 95:5, flow rate: 1.0 mL/min, tR (minor) = 11.8 min (integral = 6.8%), tR (major) = 13.3 min (integral = 93.2%). 1H-NMR (300 MHz, CDCl3) δ 7.86 (dd, J = 8.2, 5.3 Hz, 1H), 7.48 (t, J = 55.5 Hz, 1H), 7.15–7.21 (m, 2H), 4.05 (d, J = 17.9 Hz, 1H), 3.82 (s, 3H), 3.28 (d, J = 17.9 Hz, 1H). 19F-NMR (282 MHz, CDCl3) δ −91.9 (dd, J = 250.9, 56.0 Hz, 1F), −93.5 (dd, J = 250.0, 55.2 Hz, 1F), −99.6 (dd, J = 13.8 Hz, 1F). 13C-NMR (125 MHz, CDCl3) δ 194.9, 168.4, 168.0 (d, J = 259.8 Hz), 153.6 (d, J = 10.9 Hz), 128.3 (d, J = 10.9 Hz), 117.2 (d, J = 23.6 Hz), 113.2 (d, J = 22.7 Hz), 58.8, 54.2, 39.4. IR (neat): 3074, 2958, 1747, 1720, 1618, 1595, 1429, 1255, 1068, 1041 cm−1. HRMS (ESI) m/z Calcd: 313.0122 for C12H9O3F3NaS (M + Na)+ Found: 313.0120.
Ethyl 2-((difluoromethyl)thio)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3g). Yellow oil (35 mg, 61%, 85% ee). [α]25D = + 3.8 (c = 0.46, CHCl3). The ee value was determined by HPLC analysis using a Chiralpack IB3 column (hexane/iPrOH = 99:1, flow rate: 1.0 mL/min, tR (minor) = 24.5 min (integral = 7.6%), tR (major) = 27.3 min (integral = 92.4%). 1H-NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 15.9 Hz, 1H), 7.53 (t, J = 51.2 Hz, 1H), 7.45–7.50 (m, 2H), 4.29 (q, J = 7.2 Hz, 2H), 4.04 (d, J = 17.9 Hz, 1H), 3.25 (d, J = 17.9 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H). 19F-NMR (282 MHz, CDCl3) δ −91.9 (dd, J = 250.9, 56.0 Hz, 1F), −93.3 (dd, J = 250.0, 56.9 Hz, 1F). 13C-NMR (125 MHz, CDCl3) δ 197.1, 168.4, 150.7, 136.5, 133.2, 128.8, 126.4, 126.0, 120.5 (t, J = 270.7 Hz), 63.6, 58.5, 39.6, 14.1. IR (neat): 2985, 1739, 1720, 1606, 1468, 1271, 1244, 1213, 1182, 1065, 1034 cm−1. HRMS (ESI) m/z Calcd: 309.0373 for C13H12O3F2NaS (M + Na)+ Found: 309.0351.
Methyl 2-((difluoromethyl)thio)-2-Methyl-3-Oxo-3-Phenylpropanoate (3h). Colorless oil (19.5 mg, 36%, 12% ee). The ee value was determined by HPLC analysis using a Chiralpack OD-3 column (hexane/iPrOH = 99:1, flow rate: 0.53 mL/min, tR (minor) = 40.2 min (integral = 43.8%), tR (major) = 45.3 min (integral = 52.5%). 1H-NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.4 Hz, 2H), 7.56–7.61 (m, 1H), 7.43–7.48 (m, 2H), 6.89 (t, J = 55.9 Hz, 1H), 3.73 (s, 3H), 1.97 (s, 3H). 19F-NMR (282 MHz, CDCl3) δ −92.7 (d, J = 55.2 Hz, 2F). HRMS (ESI) m/z: 297 (M + Na)+.

4. Conclusions

In summary, we have described the first asymmetric electrophilic difluoromethylthiolation of β-keto esters by means of a difluoromethanesulfonyl hypervalent iodonium ylide. The traceless use of chiral amines as chiral auxiliary allowed the synthesis of enantioenriched indanone-based α-SCF2H β-keto esters in up to 93% ee value. We believe that this synthetic approach to enantiomerically enriched indanone scaffolds will create interest for the design of new biologically attractive drug candidates having α-SCF2H indanone moiety. While tetralone-type and acyclic substrates failed to react efficiently, the improvement of the results could be theoretically possible by using chiral amines with electron withdrawing groups. This investigation is ongoing in our laboratory.

Supplementary Materials

The following are available online, 1H, 13C and 19F NMR spectra of compounds 3 and HPLC data of compounds 3.

Author Contributions

N.S. conceived and designed the experiments and directed the project; S.G., O.M. and H.C. performed the experiments; S.G., O.M. and H.C. and Y.S. analyzed the data; D.C. contributed to critical discussion and presentation of the results; Y.S. checked the experimental details; D.C. and N.S. wrote the paper.

Funding

This work was partially supported by ACT-C from the JST (JPMJCR12Z7), the CNRS Project International de Coopération Scientifique (PICS) N°7262 and JSPS KAKENHI Grant-in-Aid for Scientific Research (B) Grant Number 18H02553.

Acknowledgments

We thank Juhua Group Corporation for the gift of sodium difluoromethanesulfinate.

Conflicts of Interest

The authors declare no conflicts of interest.

References and Notes

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Sample Availability: Samples of the compounds 1a, 1b, 3 are available from the authors.
Molecules 24 00221 sch001 550
Scheme 1. Two methods for the asymmetric synthesis of difluoromethylthio-compounds with a tetrasubstituted carbon center; (a) previous work; (b) this work. The asterisk indicates the chiral center in the molecules.
Scheme 1. Two methods for the asymmetric synthesis of difluoromethylthio-compounds with a tetrasubstituted carbon center; (a) previous work; (b) this work. The asterisk indicates the chiral center in the molecules.
Molecules 24 00221 sch001
Molecules 24 00221 sch002 550
Scheme 2. Difluoromethylthiolation of various indanone-based enamino esters and one acyclic enamino ester. The asterisk indicates the chiral center in the molecules 3.
Scheme 2. Difluoromethylthiolation of various indanone-based enamino esters and one acyclic enamino ester. The asterisk indicates the chiral center in the molecules 3.
Molecules 24 00221 sch002
Molecules 24 00221 sch003 550
Scheme 3. Proposed reaction mechanism. The asterisk indicates the chiral center.
Scheme 3. Proposed reaction mechanism. The asterisk indicates the chiral center.
Molecules 24 00221 sch003
Table
Table 1. Screening of chiral amines.
Table 1. Screening of chiral amines.
Molecules 24 00221 i001
EntryArR2Yield (%) 1Ee (%) 2
1PhMe2a7957
2PhEt2b7946
31-NaphthylMe2c5762
44-MeC6H4Me2d8057
54-MeOC6H4Me2e7849
1 Yields for isolated pure products. 2 Ee values were determined by HPLC analysis [35]. The asterisk indicates the chiral center in the molecule 3a.
Table
Table 2. Optimization of the reaction conditions.
Table 2. Optimization of the reaction conditions.
Molecules 24 00221 i002
EntryAr2SolventYield (%) 1Ee (%) 2
1Ph2a1,4-dioxane7957
2Ph2aTHF7556
3Ph2aCH2Cl27467
4Ph2aCHCl37568
5Ph2aToluene7669
61-Naphthyl2c1,4-dioxane5762
71-Naphthyl2cCH2Cl25288
81-Naphthyl2cCHCl36587
91-Naphthyl2cToluene5988
101-Naphthyl2cCH3CN0–
1 Yields for isolated pure products. 2 Ee values were determined by HPLC analysis [35]. The asterisk indicates the chiral center in the molecule 3a.

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MDPI and ACS Style

Gondo, S.; Matsubara, O.; Chachignon, H.; Sumii, Y.; Cahard, D.; Shibata, N. Asymmetric Electrophilic Difluoromethylthiolation of Indanone-Based β-Keto Esters Using Difluoromethanesulfonyl Hypervalent Iodonium Ylides. Molecules 2019, 24, 221. https://doi.org/10.3390/molecules24020221

AMA Style

Gondo S, Matsubara O, Chachignon H, Sumii Y, Cahard D, Shibata N. Asymmetric Electrophilic Difluoromethylthiolation of Indanone-Based β-Keto Esters Using Difluoromethanesulfonyl Hypervalent Iodonium Ylides. Molecules. 2019; 24(2):221. https://doi.org/10.3390/molecules24020221

Chicago/Turabian Style

Gondo, Satoshi, Okiya Matsubara, Hélène Chachignon, Yuji Sumii, Dominique Cahard, and Norio Shibata. 2019. "Asymmetric Electrophilic Difluoromethylthiolation of Indanone-Based β-Keto Esters Using Difluoromethanesulfonyl Hypervalent Iodonium Ylides" Molecules 24, no. 2: 221. https://doi.org/10.3390/molecules24020221

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