LDA-promoted asymmetric synthesis of β-trifluoromethyl-β-amino indanone derivatives with virtually complete stereochemical outcome

Abstract

We demonstrate that reactions between various 1-indanones and (S_S)-N-tert-butanesulfinyl-(3,3,3)-trifluoroacetaldimine, conducted in the presence of catalytic amounts of LDA, occur with virtually complete stereochemical outcome, offering reliable and generalized access to biologically relevant β-trifluoromethyl-β-amino indanone derivatives. The products can be isolated in diastereomerically pure form simply by washing the crude reaction mixture with hexanes, underscoring practicality of the present method.

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Introduction

β-Amino ketones represent one of the most extraordinary important classes of nitrogen-containing biologically relevant compounds.¹ Their chemistry has been studied by many generations of organic chemists leading to discovery and development of numerous commercial pharmaceuticals.² β-Amino ketones are also of great importance as synthetic intermediates as they can be easily converted into the corresponding γ-amino alcohols, β-amino esters, 1,3-diamines and many other multifunctional compounds.³ In particular, Mannich-type addition reactions of ketones with imino compounds, or their precursors, is one of the most straightforward synthetic approaches to β-amino carbonyl compounds.⁴ While this reaction is well-studied, its application for preparation of fluorinated β-amino carbonyl compounds has been quite limited, in particular in asymmetric mode, due to restricted availability of proper fluorine containing imines.⁵

Fluorine substitution for hydrogen is currently an established strategy in the development of new drugs with improved metabolic stability, bioavailability and protein–ligand interactions.^6,7 In particular, CF₃–CH(NH₂)-structural feature⁸ is generally used as a pharmacophore in the design of bioactive compounds. In this regard, fluorinated β-amino carbonyl compounds, especially the β-trifluoromethylated β-amino ketones were shown to play a critical role in the field of biochemistry and pharmacology.⁷ (S_S)-N-tert-Butanesulfinyl (3,3,3)-trifluoroacetaldimine 1 (Table 1), an analogue of Ellman-type imine reagents,⁹ displays high reactivity, asymmetric induction and is commercially available in both enantiomeric forms.¹⁰ In the recent years, application of reagent 1 for introduction of CF₃–CH(NH₂)-pharmacophore unit in numerous biologically relevant molecules has been quite actively pursued, as evidenced by the dramatic increase in research disclosures in the literature.¹¹ However, to the best of our knowledge, there were no reports on the reactions of imine 1 with 1-indanone derivatives. One may agree that asymmetric modification of indanone skeleton with CF₃–CH(NH₂)-group would be of great interest offering a new class of biologically relevant fluorinated β-amino ketones. In this Communication, we report a preliminary study on the addition reactions between indanone derived enolates and imine reagent 1. We demonstrate that the reactions under study proceed with virtually complete stereochemical outcome proving a generalized and practical access to the target β-trifluoromethyl β-amino ketones.

Table 1 Optimization of reaction conditions^a

Entry	Base (mol%)	Solvent	Yield (%)^b	%de of 3a^c
a Reaction condition: 1-indanone 2a (1.1 mmol), sulfinylimine 1 (1.0 mmol), base, solvent (5 mL).b Isolated yields of diastereomerically pure 3a.c Isomer ratio was determined by ^19F NMR on crude reaction mixtures.d Sulfinylimine 1 was pre-cooled to −78 °C, and then transferred via cannula to the reaction mixture.
1	LDA (100)	THF	95	88
2	n-BuLi (100)	THF	42	88
3	LiHMDS (100)	THF	83	86
4	LDA (100)	Et2O	81	30
5	LDA (100)	Toluene	89	65
6^d	LDA (100)	THF	96	>98
7^d	LDA (50)	THF	96	>98
8^d	LDA (20)	THF	94	>98

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Results and discussions

At the outset of this study, we selected unsubstituted 1-indanone 2a as a model substrate to optimize the reaction conditions (Table 1). Preliminary experiments have shown that complete conversion of imine 1 can be achieved with as little excess as 1.1 equivalents of ketone 2a. Using THF as solvent at −78 °C (entries 1–3) we screened the bases such as LDA, n-BuLi and LiHMDS. While the diastereoselectivity was quite encouraging in all cases, LDA was clearly superior in terms of chemical yield, giving rise to the desired product 3a in 95% yield (entry 1). With a goal to improve the stereochemical outcome, we studied the reactions in different solvents. Unfortunately, these attempts gave negative results, as application of any other solvent than THF led to noticeable decrease in the stereoselectivity. Two representative examples are given in entries 4 and 5. Detailed analysis of numerous peculiarities of the experimental procedures allowed us to determine that mode of the addition of imine 1 to a solution of preformed enolate of 2a has a profound effect on the stereochemical outcome. Thus, we found that sulfinylimine 1 has to be pre-cooled to −78 °C, and then transferred via cannula to the reaction mixture (entry 6). This modification of the addition procedure allowed preparation of the desired product 3a in 96% yield and with virtually complete diastereoselectivity (de > 98%). While studying various aspects of the enolate formation, we made another surprising observation. In particular, we found that LDA can be used in substoichiometric amounts. As shown in entry 7, application of 0.5 equivalents of LDA gave the same (entry 7 vs. 6) stereochemical outcome of the addition reaction under study. Furthermore, we determined that LDA can be used in as low as 0.2 equivalents without any noticeable effect on the reaction outcome (entry 8 vs. 7 and 6). Of particular importance is that the product 3a can be isolated in diastereomerically pure form without column chromatography and recrystallization. Drawing from the GAP chemistry (group-assisted purification) reported by Li group,¹² we used the recommended procedure by washing the crude mixture with hexanes.

Having optimized the reaction conditions, we studied next the generality of this method using series of 1-indanones bearing various substituents on the aromatic ring (Table 2). As shown in Table 2, electron-donating, -withdrawing and sterically bulky substituents in position 6 (entries 2–7) as well as in position 5 (entries 8–11) had very little effect on the stereochemical outcome of the addition reactions. Similar results were also obtained with substrates 2l, m bearing two substituents in the positions 5,7 or 5,6. These results clearly suggest that these reactions have a good range of generality as various substituents can be introduced on the aromatic ring for systematic biological studies. It should be emphasised that the yields reported in Tables 1 and 2 are those obtained for diastereomerically pure compounds 3a–m prepared by washing the crude products with hexanes, without application of column chromatography.

Table 2 Scope of 1-indanones for the asymmetric addition^a

Entry	R	Product	Yield (%)^b	de (%)^c
a Reaction condition: 1-indanone 2 (1.1 mmol), sulfinylimine 1 (1.0 mmol), LDA (0.2 mmol), THF (5 mL).b Isolated yields.c Isomer ratio was determined by ^19F NMR.
1	H	3a	94	98
2	6-Me	3b	91	96
3	6-tBu	3c	92	96
4	6-OMe	3d	92	93
5	6-F	3e	93	98
6	6-Cl	3f	92	98
7	6-Br	3g	93	98
8	5-OMe	3h	89	98
9	5 F	3i	95	98
10	5-Cl	3j	91	96
11	5-Br	3k	90	96
12	5,7-di-Cl	3l	85	98
13	5,6-di-OMe	3m	93	98

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To assign the absolute configuration of the two newly created stereogenic centres we performed crystallographic analysis of 3a (Fig. 1). As shown in Fig. 1, both of the stereogenic centers are of (S) absolute configuration. The absolute configuration of the rest of products 3b–m in this study were assigned based on the similarity of their spectroscopic and chiroptical properties.

Fig. 1 Crystallographic structure of (S,S)-3a.

To account for the observed preference for the absolute configuration of the products 3, we propose a plausible mechanism shown in Scheme 1. Initially, ketone enolate (A) is generated by the reaction of 1-indanone 2a with LDA. Then Mannich addition between ketone derived enolate (A) and CF₃-sulfinylimine 1 occurred via an open non-chelated transition state model to afford the intermediate (B). In this model, enolate (A) preferably added to the imine from the less hindered face to afford (S_S,S,S)-3a as major diastereomer. One may agree that, the intermediate (B) can react with another molecule of 1-indanone 2a to generate the final product 3a as well as ketone enolate (A) to carry over the catalytic cycle.

Scheme 1 Proposed mechanism for the asymmetric addition.

As the final goal of this study, we demonstrated deprotection of the addition products 3a. The N-tert-butylsulfinyl group can be conveniently cleaved by treatment with aqueous HCl in methanol under mild condition (Scheme 2).¹³ Using this standard procedure, free β-trifluoromethylated β-amino ketone 4a was obtained in high isolated yield of 87%.

Scheme 2 Conversion of 3a to free β-amino ketone 4a.

Conclusion

In summary, this work reveals that various β-trifluoromethylated β-amino indanone derivatives can be prepared in enantiomerically pure form via asymmetric addition of 1-indanone to CF₃-sulfinylimine. These addition reactions occur with virtually complete stereochemical outcome and can tolerate electron-withdrawing, -donating or sterically bulky substituents. Unusual feature of these reactions is that they can be conducted in the presence of catalytic (0.2 equiv.) amounts of LDA. Importantly, the purifications of the resulting β-trifluoromethylated β-amino indanone products 3a–m are performed via the economical and simple operation which involved merely washing the crude mixtures with hexanes, thus emphasising practicality and scalability of this method.

Experimental section

General information

All reagents were obtained from commercial suppliers and used without further purification. The reactions were conducted in a closed system with an atmosphere of N₂ and were monitored by TLC. Solvents were dried and distilled prior to use. Flash chromatography was performed using silica gel 60 (200–300 mesh). Thin layer chromatography was carried out on silica gel 60 F-254 TLC plates of 20 cm × 20 cm.

Proton NMR spectra were recorded on a 400 spectrometer. Proton chemical shifts are reported in ppm (δ) relative to internal tetramethylsilane (TMS, δ 0.0 ppm) or with the solvent reference relative to TMS employed as the internal standard (CDCl₃, δ 7.26 ppm). Data are reported as follows: chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m)], coupling constants [Hz], integration). Carbon NMR spectra were recorded at 101 MHz with complete proton decoupling. Carbon chemical shifts are reported in ppm (δ) relative to TMS with the respective solvent resonance as the internal standard (CDCl₃, δ 77.0 ppm). ¹⁹F NMR spectra were recorded with a Bruker ARX 400 spectrometer. Melting points are uncorrected. Values of optical rotation were measured on Rudolph Automatic Polarimeter A21101. Infrared spectra were obtained on Bruker Vector 22 in KBr pellets. HRMS were recorded on an Agilent 6540Q-TOF LC/MS equipped with electrospray ionization (ESI) probe operating in positive or negative ion mode.

Typical procedure for asymmetric addition of sulfinylimine

Into an oven-dried reaction vial flushed with N₂ were taken ketone 2 (1.1 mmol) and anhydrous THF (5.0 mL). The reaction vial was cooled to −78 °C and LDA (2 M in THF, 0.1 mL) was added dropwise with stirring. After 40 min at −78 °C, sulfinylimine 1 (1.0 mmol) dissolved in anhydrous THF (2 mL) was pre-cooled to −78 °C, then added dropwise to the reaction mixture. Stirring was continued at −78 °C for 4 h, then the reaction was quenched with saturated NH₄Cl (3.0 mL), followed by H₂O (5.0 mL) and the mixture was brought to room temperature. The organic layer was taken and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (1 × 30 mL) and brine solution (1 × 30 mL) and dried over anhydrous Na₂SO₄. The solvent was evaporated, and the crude mixture was co-concentrated with hexane. The solid products were washed with a minimum amount of hexanes to afford pure product without column chromatography.

(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-((S)-1-oxo-2,3-dihydro-1H-inden-2-yl)ethyl)propane-2-sulfinamide (3a). White solid (313.4 mg, yield 94%), mp 195–197 °C, [α]²⁵_D −102.7 (c = 0.52, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.76 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.3 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 4.74–4.59 (m, 1H), 3.48 (d, J = 9.6 Hz, 1H), 3.35 (dd, J = 18.6, 9.3 Hz, 1H), 3.19–3.07 (m, 2H), 0.93 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 203.5, 153.3, 136.1, 135.6, 128.0, 126.6, 125.2 (q, J_FC = 283.8 Hz), 124.1, 57.8 (q, ³J_FC = 30.5 Hz), 57.1, 47.0, 27.1, 22.2. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.11. IR (KBr): ν = 3290, 1704, 1261, 1176, 1139, 1122, 1087, 1059, 757, 737, 653 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₅H₁₈F₃NO₂SNa⁺: 356.0908, found: 356.0906.

(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-((S)-6-methyl-1-oxo-2,3-dihydro-1H-inden-2-yl)ethyl)propane-2-sulfinamide (3b). White solid (316.1 mg, yield 91%), mp 196–198 °C, [α]²⁵_D −110.9 (c = 0.52, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.55 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 4.72–4.58 (m, 1H), 3.48 (d, J = 9.8 Hz, 1H), 3.35–3.23 (m, 1H), 3.15–3.01 (m, 2H), 2.41 (s, 3H), 0.95 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 203.5, 150.6, 138.0, 136.8, 136.3, 126.2, 125.2 (q, J_FC = 282.9 Hz), 124.0, 57.9 (q, ³J_FC = 30.4 Hz), 57.1, 47.3, 26.8, 22.3, 21.1. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.13. IR (KBr): ν = 3310, 1703, 1261, 1182, 1130, 1093, 1085, 1058, 936, 830, 644 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₆H₂₀F₃NO₂SNa⁺: 370.1065, found: 370.1061.

(S)-N-((S)-1-((S)-6-(tert-Butyl)-1-oxo-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (3c). White solid (358.3 mg, yield 92%), mp 158–160 °C, [α]²⁵_D −133.2 (c = 0.60, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.76 (d, J = 1.7 Hz, 1H), 7.71 (dd, J = 8.1, 1.9 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 4.70–4.59 (m, 1H), 3.45 (d, J = 9.7 Hz, 1H), 3.36–3.24 (m, 1H), 3.14–3.02 (m, 2H), 1.34 (s, 9H), 0.92 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 203.8, 151.7, 150.7, 136.2, 133.4, 126.1, 125.2 (q, J_FC = 284.1 Hz), 120.4, 58.1 (q, ³J_FC = 30.4 Hz), 57.2, 47.4, 34.9, 31.3, 26.7, 22.2. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.10. IR (KBr): ν = 3289, 2959, 1701, 1366, 1260, 1181, 1126, 1094, 1087, 640 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₉H₂₆F₃NO₂SNa⁺: 412.1534, found: 412.1530.

(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-((S)-6-methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)ethyl)propane-2-sulfinamide (3d). White solid (334.3 mg, yield 92%), mp 174–176 °C, [α]²⁵_D −140.4 (c = 0.87, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 2.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 4.70–4.59 (m, 1H), 3.84 (s, 3H), 3.60 (d, J = 9.7 Hz, 1H), 3.27 (dd, J = 16.5, 7.6 Hz, 1H), 3.16-3.02 (m, 2H), 0.95 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 203.4, 159.8, 146.2, 137.3, 127.3, 125.2 (q, J_FC = 284.1 Hz), 124.9, 105.2, 58.0 (q, ³J_FC = 30.4 Hz), 57.1, 55.6, 47.7, 26.4, 22.3. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.14. IR (KBr): ν = 3309, 1710, 1496, 1327, 1287, 1191, 1145, 1127, 1082, 1061, 1022, 821, 732, 647 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₆H₂₀F₃NO₃SNa⁺: 386.1014, found: 386.1009.

(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-((S)-6-fluoro-1-oxo-2,3-dihydro-1H-inden-2-yl)ethyl)propane-2-sulfinamide (3e). White solid (326.8 mg, yield 93%), mp 178–180 °C, [α]²⁵_D −102.0 (c = 0.71, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.52 (dd, J = 8.1, 4.5 Hz, 1H), 7.43–7.35 (m, 2H), 4.71–4.60 (m, 1H), 3.55 (d, J = 9.6 Hz, 1H), 3.33 (dd, J = 16.5, 7.5 Hz, 1H), 3.22–3.07 (m, 2H), 0.96 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 202.6 (d, ⁵J_FC = 3.0 Hz), 162.5 (d, J_FC = 249.4 Hz), 148.7 (d, ⁵J_FC = 1.7 Hz), 137.8 (d, ⁴J_FC = 7.5 Hz), 128.1 (d, ⁴J_FC = 8.0 Hz), 125.1 (q, J_FC = 283.8 Hz), 123.4 (d, ³J_FC = 23.8 Hz), 109.9 (d, ³J_FC = 22.1 Hz), 57.9 (q, ³J_FC = 30.5 Hz), 57.2, 47.9, 26.6, 22.2. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.08, −113.23. IR (KBr): ν = 3303, 1704, 1490, 1267, 1259, 1175, 1123, 1083, 829, 772, 643 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₅H₁₇F₄NO₂SNa⁺: 374.0814, found: 374.0809.

(S)-N-((S)-1-((S)-6-Chloro-1-oxo-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (3f). White solid (338.4 mg, yield 92%), mp 198–200 °C, [α]²⁵_D −138.4 (c = 0.62, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.72 (d, J = 1.3 Hz, 1H), 7.61 (dd, J = 8.2, 1.8 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 4.72–4.59 (m, 1H), 3.51 (d, J = 9.5 Hz, 1H), 3.39–3.25 (m, 1H), 3.21–3.05 (m, 2H), 0.97 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 202.1, 151.3, 137.5, 135.6, 134.5, 127.8, 125.1 (q, J_FC = 283.8 Hz), 123.8, 57.8 (q, ³J_FC = 30.6 Hz), 57.2, 47.6, 26.8, 22.3. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.05. IR (KBr): ν = 3299, 1702, 1323, 1258, 1180, 1128, 1084, 924, 673 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₅H₁₇ClF₃NO₂SNa⁺: 390.0518, found: 390.0512.

(S)-N-((S)-1-((S)-6-Bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (3g). White solid (383.4 mg, yield 93%), mp 188–190 °C, [α]²⁵_D −139.0 (c = 0.61, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 1.7 Hz, 1H), 7.75 (dd, J = 8.1, 1.9 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 4.71–4.59 (m, 1H), 3.48 (d, J = 9.5 Hz, 1H), 3.30 (dd, J = 17.1, 7.9 Hz, 1H), 3.19–3.03 (m, 2H), 0.97 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 202.1, 151.8, 138.3, 137.8, 128.2, 126.9, 125.1 (q, J_FC = 284.1 Hz), 122.2, 57.8 (q, ³J_FC = 30.5 Hz), 57.2, 47.5, 26.9, 22.3. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.04. IR (KBr): ν = 3297, 1708, 1258, 1182, 1128, 1083, 956, 920, 828, 662 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₅H₁₇BrF₃NO₂SNa⁺: 434.0013, found: 434.0007.

(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-((S)-5-methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)ethyl)propane-2-sulfinamide (3h). White solid (323.4 mg, yield 89%), mp 216–218 °C, [α]²⁵_D −48.0 (c = 0.67, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.69 (d, J = 9.1 Hz, 1H), 6.97–6.89 (m, 2H), 4.71–4.56 (m, 1H), 3.91 (s, 3H), 3.47 (d, J = 9.8 Hz, 1H), 3.35–3.22 (m, 1H), 3.15–3.00 (m, 2H), 0.95 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 201.3, 165.9, 156.3, 129.5, 125.8, 125.3 (q, J_FC = 283.8 Hz), 116.0, 109.6, 58.0 (q, ³J_FC = 30.4 Hz), 57.1, 55.8, 47.0, 27.2, 22.2. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.09. IR (KBr): ν = 3273, 1694, 1605, 1316, 1279, 1262, 1173, 1143, 1124, 1087, 1039, 843, 646 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₆H₂₀F₃NO₃SNa⁺: 386.1014, found: 386.1009.

(S)-2-Methyl-N-((S)-2,2,2-trifluoro-1-((S)-5-fluoro-1-oxo-2,3-dihydro-1H-inden-2-yl)ethyl)propane-2-sulfinamide (3i). White solid (333.8 mg, yield 95%), mp 216–218 °C, [α]²⁵_D −96.5 (c = 0.80, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.78 (dd, J = 8.5, 5.3 Hz, 1H), 7.20 (dd, J = 8.3, 1.6 Hz, 1H), 7.12 (td, J = 8.6, 2.1 Hz, 1H), 4.72–4.59 (m, 1H), 3.49 (d, J = 9.4 Hz, 1H), 3.34 (dd, J = 18.7, 9.5 Hz, 1H), 3.22–3.06 (m, 2H), 0.96 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 201.5, 167.6 (d, J_FC = 258.1 Hz), 156.2 (d, ⁴J_FC = 10.3 Hz), 132.6 (d, ⁵J_FC = 1.7 Hz), 126.5 (d, ⁴J_FC = 10.6 Hz), 125.1 (q, J_FC = 283.8 Hz), 116.5 (d, ³J_FC = 23.8 Hz), 113.3 (d, ³J_FC = 22.5 Hz), 57.8 (q, ³J_FC = 30.5 Hz), 57.2, 47.3, 27.2, 22.2. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.06, −100.87. IR (KBr): ν = 3294, 1708, 1620, 1595, 1426, 1333, 1321, 1308, 1270, 1261, 1252, 1176, 1140, 1131, 1124, 1083, 1060, 1033, 848, 787, 643, 619 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₅H₁₇F₄NO₂SNa⁺: 374.0814, found: 374.0810.

(S)-N-((S)-1-((S)-5-Chloro-1-oxo-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (3j). White solid (334.7 mg, yield 91%), mp 218–220 °C, [α]²⁵_D −42.5 (c = 0.65, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.70 (d, J = 8.2 Hz, 1H), 7.53 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.73–4.58 (m, 1H), 3.53 (d, J = 9.4 Hz, 1H), 3.33 (dd, J = 18.5, 9.4 Hz, 1H), 3.21–3.05 (m, 2H), 0.96 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 201.9, 154.7, 142.2, 134.6, 128.9, 126.8, 125.2, 125.1 (q, J_FC = 283.8 Hz), 57.8 (q, ³J_FC = 30.4 Hz), 57.2, 47.2, 26.9, 22.3. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.04. IR (KBr): ν = 3297, 1708, 1604, 1427, 1322, 1267, 1258, 1180, 1142, 1127, 1084, 1063, 916, 668 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₅H₁₇ClF₃NO₂SNa⁺: 390.0518, found: 390.0514.

(S)-N-((S)-1-((S)-5-Bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (3k). White solid (375.2 mg, yield 90%), mp 202–204 °C, [α]²⁵_D −30.8 (c = 0.64, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.71 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 4.72–4.58 (m, 1H), 3.56 (d, J = 9.5 Hz, 1H), 3.40–3.26 (m, 1H), 3.20–3.06 (m, 2H), 0.96 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 202.2, 154.8, 134.9, 131.7, 131.1, 129.9, 125.2, 125.1 (q, J_FC = 283.8 Hz), 57.8 (q, ³J_FC = 30.5 Hz), 57.2, 47.1, 26.9, 22.3. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.02. IR (KBr): ν = 3296, 1709, 1599, 1321, 1258, 1185, 1143, 1130, 1084, 1062, 664 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₅H₁₇BrF₃NO₂SNa⁺: 434.0013, found: 434.0008.

(S)-N-((S)-1-((S)-5,7-Dichloro-1-oxo-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (3l). White solid (341.9 mg, yield 85%), mp 210–212 °C, [α]²⁵_D −134.4 (c = 0.62, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.42 (s, 1H), 7.37 (s, 1H), 4.74–4.58 (m, 1H), 3.48 (d, J = 9.5 Hz, 1H), 3.30 (dd, J = 17.1, 8.0 Hz, 1H), 3.21–3.04 (m, 2H), 0.99 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 199.0, 156.4, 142.1, 133.2, 130.8, 129.9, 125.3, 125.0 (q, J_FC = 283.8 Hz), 58.0 (q, ³J_FC = 30.6 Hz), 57.3, 47.8, 26.6, 22.2. ¹⁹F NMR (376 MHz, CDCl₃): δ −72.84. IR (KBr): ν = 3295, 1712, 1589, 1569, 1320, 1257, 1233, 1189, 1135, 1127, 1083, 928, 836, 669 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₅H₁₆Cl₂F₃NO₂SNa⁺: 424.0129, found: 424.0123.

(S)-N-((S)-1-((S)-5,6-Dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (3m). White solid (365.9 mg, yield 93%), mp 209–211 °C, [α]²⁵_D −77.1 (c = 0.63, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.16 (s, 1H), 6.94 (s, 1H), 4.70–4.56 (m, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 3.54 (d, J = 9.7 Hz, 1H), 3.24 (dd, J = 16.5, 7.3 Hz, 1H), 3.14–2.99 (m, 2H), 0.96 (s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ 201.8, 156.2, 149.9, 148.9, 129.1, 125.3 (q, J_FC = 284.1 Hz), 107.3, 104.3, 58.0 (q, ³J_FC = 30.3 Hz), 57.1, 56.4, 56.2, 47.1, 26.9, 22.3. ¹⁹F NMR (376 MHz, CDCl₃): δ −73.08. IR (KBr): ν = 3237, 1686, 1590, 1509, 1318, 1270, 1264, 1179, 1128, 1088, 1040, 854, 654 cm⁻¹. HRMS [M+Na⁺]: calcd for C₁₇H₂₂F₃NO₄SNa⁺: 416.1119, found: 416.1114.

Conversion of 3a affording free β-amino ketone 4a

3a (0.5 mmol) and MeOH (5 mL) were placed in a 25 mL round-bottom flask and aq HCl (36%, 1 mL) was added. The reaction was stirred at rt for 8 h, during which the cleavage was monitored by TLC. Volatiles were removed under reduced pressure. The residue was dissolved in CH₂Cl₂ (10 mL) and Et₃N (15 mmol) was added. The mixture was stirred at rt for 1 h, then H₂O (10 mL) was added. The organic layer was taken, washed with H₂O (2 × 10 mL), dried with anhydrous Na₂SO₄, filtered and the solvent was removed to give the crude product, which was purified by TLC plate.

(S)-2-((S)-1-Amino-2,2,2-trifluoroethyl)-2,3-dihydro-1H-inden-1-one (4a). White solid (99.7 mg, yield 87%), mp 72–74 °C, [α]²⁵_D −54.4 (c = 0.18, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 7.7 Hz, 1H), 7.62 (td, J = 7.6, 1.2 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.42–7.36 (m, 1H), 4.13 (qd, J = 8.3, 2.3 Hz, 1H), 3.26–3.21 (m, 2H), 3.06–3.00 (m, 1H), 1.38 (s, 2H). ¹³C NMR (101 MHz, CDCl₃): δ 204.9, 154.0, 136.3, 135.3, 127.7, 126.6 (q, J_FC = 282.5 Hz), 126.6, 124.1, 52.5 (q, ³J_FC = 29.4 Hz), 47.3, 26.4. ¹⁹F NMR (376 MHz, CDCl₃): δ −76.20. IR (KBr): ν = 3390, 2933, 1712, 1606, 1466, 1329, 1280, 1265, 1202, 1158, 1112, 919, 869, 757, 649 cm⁻¹. HRMS [M+H]: calcd for C₁₁H₁₁F₃NO⁺: 230.0793, found: 230.0778.

Acknowledgements

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (no. 21102071) and the Fundamental Research Funds for the Central Universities (no. 1107020522 and no. 1082020502). The Jiangsu 333 program (for Pan) and Changzhou Jin-Feng-Huang program (for Han) are also acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, full spectroscopic data for new compounds 3, 4 and copies of ¹H NMR and ¹³C NMR spectra. CCDC 951194. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra45773g

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