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Article

Organocatalyzed Enantioselective [3+2] Cycloaddition Reactions for Synthesis of Dispiro[benzothiophenone-indandione-pyrrolidine] Derivatives

by
Hong-Yan Liu
1,2 and
Da-Ming Du
1,2,*
1
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, No. 5 Zhongguancun South Street, Beijing 100081, China
2
Key Laboratory of Medicinal Molecule Science and Pharmaceutical Technology, Ministry of Industry and Information Technology, No. 5 Zhongguancun South Street, Beijing 100081, China
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(20), 4856; https://doi.org/10.3390/molecules29204856
Submission received: 18 September 2024 / Revised: 10 October 2024 / Accepted: 11 October 2024 / Published: 13 October 2024
(This article belongs to the Special Issue Advances in Asymmetric Tandem Reactions)
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Abstract

:
An organocatalytic enantioselective [3+2] cycloaddition reaction involving 2-arylidene-1,3-indandiones and N-2,2-difluoroethylbenzothiophenone imines was developed. This approach efficiently afforded dispiro[benzothiophenone-indandione-pyrrolidine]s, featuring three stereocenters, in 84–98% yields with 3–93% ee and 9:1–>20:1 dr. Notably, the method maintained its yield and enantioselectivity integrity even in a gram-scale amplification experiment. For example, the product with substituents on aromatics were obtained in 90% yield with 91% ee and >20:1 dr. Its absolute configuration was established through X-ray single-crystal diffraction analysis, and a plausible reaction mechanism was proposed.

1. Introduction

In recent years, chiral spiroindanone compounds have garnered significant attention due to their remarkable bioactivities exhibiting numerous potential pharmacological effects. Among them, spiroisoquinolines have attracted particular interest for their sedative, antihypertensive, and neuromuscular blocking activities. Bisphenyl spiroketones, on the other hand, are emerging as novel anticancer agents, offering new directions for the development of anticancer drugs. Moreover, Fredericamycin A, a notable antitumor compound with significant antibiotic properties, has demonstrated immense potential in clinical medicine [1,2,3] (Figure 1). Given the immense value of chiral spiroindanone compounds in the fields of clinical medicine and medicinal chemistry, their construction has remained a hotspot in asymmetric catalytic synthesis.
2-Arylidene-1,3-indandione, a planar compound, features both its indandione and arylidene moieties as potential electrophilic centers susceptible to nucleophilic attack, and the central carbon can be transformed to nucleophilic in reaction progress (Figure 2). Its 1,3-indandione scaffold bears three consecutive reactive sites, enabling self-condensation to form homodimers and cyclotrimers. The electrophilicity of its arylidene part renders it a Michael acceptor, participating in annulation reactions to yield six-membered rings, enhancing structural diversity. Furthermore, it undergoes dipolar cycloaddition with 1,3-dipoles, yielding five-membered rings. Toxicity modulation is achievable by introducing diverse polar groups onto the aryl ring [4,5,6,7]. These properties make 2-arylidene-1,3-indandione highly sought-after in synthetic chemistry and drug development. Notably, it also demonstrates promising prospects in constructing biologically active spirocyclic scaffolds using nucleophilicity of the central carbon and allowing the [3+2] cycloaddition [8,9,10,11,12,13,14,15]. For example, in 2022, our group achieved an asymmetric [3+2] cyclization reaction between 2-arylidene-1,3-indanediones and isothiocyanatoindanones catalyzed by squaramide in chloroform, and thiodispiro[indene-pyrrolidine-indene]-trione compounds with two consecutive stereogenic centers were obtained [16] (Scheme 1a). This reaction exhibited high yields and excellent stereoselectivities. In 2023, Zhou and coworkers delved into a mild and efficient organocatalytic [3+2] cycloaddition reaction between isatin-derived ketimines and 2-ylideneindane-1,3-diones [17] (Scheme 1b), spiro[oxindole-3,2′-pyrrolidine]s compounds that integrate both the spiroindane-1,3-dione motif and trifluoromethyl, two crucial structural units were successfully constructed. This reaction proceeded with high yields and displayed good diastereoselectivities and enantioselectivities. Moreover, in 2023, Lei and his team successfully utilized squaramide-catalyzed [2+1] cycloaddition to synthesize a series of compounds featuring a dispiro[indanedione-oxindole-cyclopropane] scaffold [18] (Scheme 1c), starting from 2-arylidene-1,3-indanediones and 3-bromooxindoles. This reaction system proceeded through an efficient tandem Michael/alkylation pathway, and the products were obtained with excellent diastereoselectivities and enantioselectivities.
Furthermore, the introduction of fluorine groups as an effective molecular modification approach profoundly impacts the physical, chemical, biological, and pharmacokinetic properties of organic molecules [19]. Notably, the selective replacement of hydrogen atoms in methyl groups with fluorine atoms to form difluoromethyl groups (–CF2H) exerts a pivotal role in drug-biological target interactions due to their weak acidity as hydrogen bond donors [20]. Molecules containing the –CF2H group exhibit significant advantages in enhancing drug efficacy, attributed to their heightened binding affinity [21]. However, given the pronounced differences in properties between –CF3 and –CF2H, studies on 1,3-dipoles featuring –CF2H are relatively scarce, motivating our dedication to exploring this area.
Inspired by this, herein, we developed an organocatalyzed enantioselective [3+2] cycloaddition to construct chiral dispiro[benzothiophenone-indandione-pyrrolidine] compounds (Scheme 1d) using 2-arylidene-1,3-indandiones and 2-((2,2-difluoroethyl)imino)benzo[b]thiophen-3(2H)-ones, aiming to contribute efficient and safe new drug candidates to the pharmaceutical research field through this innovative strategy.

2. Results and Discussion

2.1. Optimization of Reaction Conditions

Using 2-arylidene-1,3-indandione 1a and 2-((2,2-difluoroethyl)imino)benzo[b]thiophen-3(2H)-one 2a as the template substrates, we embarked on a systematic investigation to identify the optimal reaction parameters through a rigorous evaluation of various reaction conditions. The objective was to establish a robust synthetic protocol for the target compounds, backed by sound experimental data. Initially, dichloromethane served as the solvent medium, using 10 mol% of quinine-derived bis(trifluoromethyl)-substituted squaramide C1 as catalyst (depicted in Figure 3). The reaction was carried out at ambient temperature over a period of 24 h. Subsequent analysis revealed that these conditions facilitated the formation of a dispiro[benzothiophenone-pyrrolidine-indandione] derivative in 80% yield with 20:1 dr and 76% ee. Having validated the identity of the desired product, we proceeded to evaluate the catalytic efficacy of alternative catalysts under identical experimental settings. The outcomes of these experiments are concisely presented in Table 1, facilitating a comparative assessment of catalyst performance.
Through screening of quinine-derived squaramide catalysts, it was found that catalyst C2 had similar catalytic effects as C1, and although the yield of 3aa was improved using C3, its enantiomeric excess decreased significantly. After using hydroquinine-derived squaramide C4 and cinchonidine-derived squaramide catalyst C5, the enantiomeric excess did not improve. Subsequently, the use of hydroquinidine-derived catalyst C6 did not exhibit good catalytic effects. Therefore, attention was turned to thiourea catalysts C7–C11, with the hope of finding a more effective catalytic system. Through experimental attempts, it was pleasantly surprised to find that the 4-trifluoromethylphenyl-substituted thiourea catalyst C9 exhibited excellent enantiomeric excess in this reaction. To more comprehensively evaluate the performance of different catalysts, quinine and cyclohexanediamine catalysts were also tested and compared with the thiourea catalysts. After careful comparison, C9 was ultimately selected as the optimal catalyst for this experiment, as it exhibited good catalytic activity while enhancing enantiomeric excess.
After determining the optimal catalyst as C9, further screenings of solvents, catalyst loading, and reaction temperature were conducted to optimize the reaction conditions. Initially, eight different solvents including chloroform, 1,2-dichloroethane (DCE), toluene, acetonitrile, tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), dioxane, and diethyl ether were tested (Table 1, entries 9, 12–19). Under identical experimental conditions, it was found that dichloromethane remained the best solvent for this reaction, providing the highest yield and enantioselectivity. Subsequently, the influence of catalyst loading and temperature on the reaction was investigated. The experimental results showed that neither increasing nor decreasing the catalyst loading significantly improved the enantioselectivity. This indicated that 10 mol% catalyst loading of the C9 was already sufficiently effective in the current reaction system. Then, the reaction temperature was lowered to −10 °C. Although the enantioselectivity of the reaction was well maintained at this temperature, the reaction time significantly increased and the yield decreased. Therefore, considering the balance between yield and enantioselectivity, it was decided to maintain room temperature as the reaction temperature.
In summary, the optimal reaction conditions for this asymmetric [3+2] cycloaddition reaction of 1a and 2a were established as: 10 mol% of 4-trifluoromethylphenyl-substituted thiourea C9 as the catalyst, 2 mL of dichloromethane as the solvent, and the reaction was conducted at room temperature.

2.2. Substrate Scope

Under the optimized reaction conditions, a systematic study was conducted on the substrate scope of the asymmetric [3+2] cycloaddition reaction, and the results are summarized in Scheme 2.
Firstly, the focus was placed on the substrate diversity of 2-arylidene-1,3-indandione. Experimental data indicated that the reaction exhibited high yields (84−98% yield) in most cases, yet the enantioselectivity was influenced by electronic effects. Specifically, when the substituent was a methyl group with electron-donating properties, the meta- and para-substitutions significantly affected the enantioselectivity of the products. Compared to the para-substituted product 3ca, the meta-substituted product 3ba exhibited significantly better enantioselectivity. Furthermore, when the methyl group was replaced by a methoxy group with a stronger electron-donating effect, the ortho- and meta-substituted products showed relatively poor enantioselectivity (22−36% ee), while the para-substituted methoxy product 3da exhibited relatively better enantioselectivity (68% ee).
Subsequently, the influence of electron-withdrawing groups on the reaction was further investigated. The experimental results showed that electron-withdrawing groups such as fluorine, chlorine, and bromine substituted at the para-position exhibited relatively poor tolerance to the reaction, and the resulting products 3ga–3ia generally had low enantioselectivity (24−41% ee). However, when the bromine atom was located at the meta-position, although the yield slightly decreased (84% yield), the enantioselectivity significantly improved (81% ee). This finding encouraged us to explore more meta-substituted substrates; unfortunately, the experimental result for substrate bearing meta-disubstituted chlorine atoms was not ideal (14% ee). When using para-nitro-substituted substrate, the enantioselectivity of product 3la was moderate (51% ee). In addition, substrates with different heterocyclic substituents were also evaluated. Among the heterocyclic substituted substrates such as thiophene, furan, and pyridine, the thiophene-substituted product 3ma exhibited relatively ideal results (88% yield and 81% ee).
To further explore the substrate scope of the asymmetric tandem reaction, the research focus was shifted to the substrate diversity of N-2,2-difluoroethylbenzothiophenone imine 2. The experimental results indicate that when N-2,2-difluoroethylbenzothiophenone imine bearing an electron-donating methyl group, the reaction proceeded smoothly, generating the corresponding product 3ba. The reaction still maintained a good yield (91% yield), but in terms of enantioselectivity, the performance of product 3ba was relatively moderate, only reaching 49% ee. Subsequently, the reaction substrates were expended to N-2,2-difluoroethylbenzothiophenone imine 2 bearing electron-withdrawing groups. The experimental results show that when introducing electron-withdrawing groups such as chlorine and fluorine atoms, the reaction did not produce the corresponding target products. This finding indicates that electron-withdrawing groups have a significant inhibitory effect on the reaction, leading to the inability to obtain the expected product.

2.3. Scaled-Up Synthesis

To validate the synthetic practicability and potential of this asymmetric [3+2] cycloaddition reaction strategy, a scale-up experiment was conducted under optimized conditions (as shown in Scheme 3). The experimental results demonstrated that even with the enlarged reaction scale, the strategy remained highly efficient and maintained excellent yield and stereoselectivity (90% yield, >20:1 dr, 91% ee). This result showcases the remarkable application value of this strategy in the large-scale asymmetric synthesis of such dispirocyclic benzothiophenone-indandione-pyrrolidine derivatives, providing strong potential for future practical applications and drug development.

2.4. X-ray Diffraction Analysis

The single crystal of 3aa was obtained by slowly evaporating the solvent from ethyl acetate, and the absolute configuration of compound 3aa was determined to be (2S,4′S,5′S) (see Supplementary Materials) through single-crystal X-ray diffraction technology (Figure 4) [22]. The absolute configurations of other products were determined by analogy.

2.5. Plausible Mechanism

Based on the previous work, we proposed a reasonable catalytic reaction mechanism (Scheme 4). In the initial stage of the Michael addition, the catalyst C9 activates the N-2,2-difluoroethylbenzothiophenone imine 2a through protonation, thereby facilitating the formation of the transition state A. Subsequently, 1a and 2a are effectively activated under the hydrogen bonding interaction of the catalyst C9. Immediately thereafter, the deprotonated 2a attacks the 2-aryl-1,3-indandione 1a from the Si-face, traversing through the transition state B to complete the intermolecular Michael addition. Following this, the resulting 2-aryl-1,3-indandione anion serves as a nucleophile in the Mannich cyclization reaction, attacking the C=N double bond of the benzothiophenone imine via the transition state C. Through this crucial step, the observed dispirocyclic product 3aa is ultimately formed. Concurrently, the deprotonation process also occurs, enabling the regeneration of the bifunctional catalyst C9. Alternatively, a concert 1,3-dipolar [3+2] cycloaddition mechanism may also be possible for this asymmetric catalytic reaction.

3. Materials and Methods

3.1. General Information

Commercially sourced compounds were used as received without any additional purification. Solvents were dried following commonly used drying methods. The isolation of products was performed on column chromatography utilizing silica gel (200–300 mesh). Melting points were ascertained with a WRX-4 melting point apparatus and without correction. 1H NMR spectra were acquired on a Bruker Ascend 400 MHz spectrometer (Bruker, Karlsurhe, Germany), and the chemical shifts were reported in δ (ppm), using tetramethylsilane (TMS) as the internal standard. 13C NMR spectra were measured at 100 MHz with a 400 MHz spectrometer, and the chemical shifts were referenced to tetramethylsilane and the deuterated solvent peak (CDCl3, δC = 77.00 ppm; DMSO-d6, δC = 39.43 ppm). High-resolution mass spectra were measured with an Agilent 6520 Accurate-Mass Q-TOF MS equipment (Agilent, Santa Clara, CA, USA) using an electrospray ionization system (ESI+). Optical rotations of chiral products were measured with a Krüss P8000 polarimeter (KRÜSS, Hamburg, Germany), and the concentration unit was reported as g/100 mL. The enantiomeric excesses of chiral products were determined with chiral HPLC analysis using an Agilent 1200 LC instrument (Agilent, Santa Clara, CA, USA) on a Daicel Chiralpak IC, or AD-H column.

3.2. Materials

2-Arylidene-1,3-indandiones 1a–1o were prepared according to the literature reported by Yang et al. [23], and N-2,2-difluoroethylbenzothiophenone imines 2a–2d were prepared according to the literature by Sun et al. [24]. The chiral organocatalysts were prepared following the procedures previously reported [25,26,27,28,29].

3.3. Procedure for the Asymmetric Synthesis of Compounds 3

2-Arylidene-1,3-indandione 1 (0.10 mmol), N-2,2-difluoroethylbenzothiophenone imine 2 (0.10 mmol), organocatalyst C9 (4.8 mg, 0.01 mmol, 10 mol%), and CH2Cl2 (2.0 mL) were sequentially added to a small, dried glass bottle. The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel (200–300 mesh) flash column chromatography using ethyl acetate/petroleum ether (1:7) as eluent. The pure products 3 were obtained. The corresponding racemate sample was prepared following a similar procedure with Et3N (10 mol%).
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-phenyl-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3aa). From 1a (23.4 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3aa (43.8 mg, 95% yield) was obtained as a white solid, m.p. 215–217 °C. HPLC (Daicel Chiralpak IC column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 9.5 min (minor), tR = 12.0 min (major); 93% ee. [α]D25 = −8.1 (c = 0.54, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.6 Hz, 1H, ArH), 7.79 (d, J = 7.2 Hz, 1H, ArH), 7.69–7.60 (m, 3H, ArH), 7.45–7.41 (m, 1H, ArH), 7.22 (t, J = 7.6 Hz, 1H, ArH), 7.10 (d, J = 7.2 Hz, 2H, ArH), 7.06–6.98 (m, 4H, ArH), 6.25 (td, J1 = 56.8, J2 = 6.8 Hz, 1H, CF2H), 4.82 (d, J = 10.0 Hz, 1H, CH), 4.72–4.63 (m, 1H, CH), 3.36 (br s, 1H, NH) ppm. 13C NMR (100MHz, CDCl3): δ 200.4, 198.7, 196.1, 147.4, 142.5, 142.1, 136.3, 136.1, 135.8, 132.7, 129.1, 128.5, 128.4, 127.9, 127.6, 125.9, 123.5, 123.21, 123.17, 118.1 (t, 1JC–F = 241.9 Hz), 81.2, 71.2, 62.2 (dd, 2JC–F = 27.3, 21.3 Hz), 51.9 (d, 3JC–F = 7.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.2 (d, J = 288.4 Hz, 1F), −121.8 (d, J = 288.8 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C26H18F2NO3S [M + H]+ 462.0970, found 462.0957.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(m-tolyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ba). From 1b (24.8 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ba (42.8 mg, 90% yield) was obtained as a white solid, m.p. 193–195 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 11.9 min (major), tR = 23.2 min (minor); 48% ee. [α]D25 = −189.6 (c = 0.75, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.2 Hz, 1H, ArH), 7.78 (d, J = 7.6 Hz, 1H, ArH), 7.69–7.59 (m, 3H, ArH), 7.45–7.40 (m, 1H, ArH), 7.21 (t, J = 7.6 Hz, 1H, ArH), 7.03 (d, J = 8.0 Hz, 1H, ArH), 6.95–6.86 (m, 3H, ArH), 6.80 (d, J = 6.8 Hz, 1H, ArH), 6.24 (td, J1 = 56.8 Hz, J2 = 6.5 Hz, 1H, CF2H), 4.78 (d, J = 9.6 Hz, 1H, CH), 4.69–4.61 (m, 1H, CH), 3.35 (br s, 1H, NH), 2.11 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 200.5, 198.7, 196.2, 147.4, 142.5, 142.2, 138.0, 136.2, 136.1, 135.7, 132.6, 129.2, 129.1, 128.7, 128.3, 127.6, 125.9, 125.4, 123.5, 123.12, 123.05, 118.1 (t, 1JC–F = 242.0 Hz), 81.2, 71.2, 62.1 (dd, 2JC–F = 27.2, 21.4 Hz), 51.9 (d, 3JC–F = 7.5 Hz), 21.2. 19F NMR (376 MHz, CDCl3): δ −117.2 (d, J = 288.4 Hz, 1F), −121.7 (d, J = 288.0 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C27H20F2NO3S [M + H]+ 476.1127, found 476.1118.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(p-tolyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ca). From 1c (24.8 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ca (42.8 mg, 90% yield) was obtained as a white solid, m.p. 164–165 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 13.9 min (major), tR = 29.7 min (minor); 3% ee. [α]D25 = −128.2 (c = 0.29, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.81 (t, J = 7.4 Hz, 2H, ArH), 7.70–7.60 (m, 3H, ArH), 7.42 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H, ArH), 7.21 (t, J = 7.2 Hz, 1H, ArH), 7.02 (d, J = 7.6 Hz, 1H, ArH), 6.98 (d, J = 8.4 Hz, 2H, ArH), 6.84 (d, J = 8.0 Hz, 2H, ArH), 6.23 (dd, J1 = 56.8, J2 = 6.8 Hz, 1H, CF3H), 4.78 (d, J = 9.6 Hz, 1H, CH), 4.68–4.60 (m, 1H, CH), 3.32 (br s, 1H, NH), 2.10 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 200.4, 198.8, 196.2, 147.4, 142.6, 142.2, 137.6, 136.2, 136.1, 135.8, 134.5, 129.64, 129.59, 129.2, 128.3, 127.6, 125.9, 123.5, 123.23, 123.17, 118.1 (t, 1JC–F = 241.8 Hz), 81.3, 71.1, 62.3 (dd, 2JC–F = 27.2, 21.2 Hz), 51.5 (d, 3JC–F = 7.5 Hz), 20.9 ppm. 19F NMR (376 MHz, CDCl3): δ −117.1 (d, J = 288.4 Hz, 1F), −121.8 (d, J = 288.4 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C27H20F2NO3S [M + H]+ 476.1127, found 476.1126.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(4-methoxyphenyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3da). From 1d (26.4 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3da (46.6 mg, 95% yield) was obtained as a white solid, m.p. 199–201 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 16.8 min (major), tR = 32.9 min (minor); 68% ee. [α]D25 = −36.0 (c = 0.17, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.82 (t, J = 7.6 Hz, 2H, ArH), 7.71–7.61 (m, 3H, ArH), 7.43 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H, ArH), 7.23–7.19 (m, 1H, ArH), 7.03 (d, J = 8.0 Hz, 1H, ArH), 6.96 (t, J = 7.8 Hz, 1H, ArH), 6.69 (d, J = 7.6 Hz, 1H, ArH), 6.62 (s, 1H, ArH), 6.54 (dd, J1 = 8.2 Hz, J2 = 2.2 Hz, 1H, ArH), 6.24 (td, J1 = 56.6 Hz, J2 = 6.8 Hz, 1H, CF2H), 4.79 (d, J = 9.6 Hz, 1H, CH), 4.68–4.60 (m, 1H, CH), 3.63 (s, 3H, OCH3), 3.27 (br s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.5, 198.6, 196.1, 159.3, 147.5, 142.5, 142.2, 136.3, 136.2, 135.8, 134.3, 129.5, 129.1, 127.6, 125.9, 123.5, 123.2, 123.1, 120.7, 118.1 (t, 1JC–F = 242.1 Hz), 113.9, 113.8, 81.2, 71.1, 62.2 (dd, 2JC–F = 27.2, 21.4 Hz), 55.1, 51.9 (d, 3JC–F = 7.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.3 (d, J = 288.4 Hz, 1F), −121.8 (d, J = 288.4 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C27H20F2NO4S [M + H]+ 492.1076, found 492.1078.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(2-methoxyphenyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ea). From 1e (26.4 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ea (46.2 mg, 94% yield) was obtained as a white solid, m.p. 186–188 °C. HPLC (Daicel Chiralpak IC column, mobile phase n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 10.6 min (major), tR = 13.2 min (minor); 22% ee. [α]D25 = −2.1 (c = 0.49, CH2Cl2). 1H NMR (700 MHz, CDCl3): δ 7.90 (dd, J1 = 7.7 Hz, J2 = 0.8 Hz, 1H, ArH), 7.70 (d, J = 7.7 Hz, 1H, ArH), 7.63 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H, ArH), 7.59–7.55 (m, 2H, ArH), 7.45 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H, ArH), 7.27 (d, J = 7.7 Hz, 1H, ArH), 7.59–7.22 (m, 1H, ArH), 6.95 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H, ArH), 6.79 (td, J1 = 7.7 Hz, J2 = 0.7 Hz, 1H, ArH), 6.38–6.20 (m, 2H, ArH + CF2H), 5.22 (d, J = 9.8 Hz, 1H, CH), 4.71–4.65 (m, 1H, CH), 3.45 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 201.5, 198.6, 194.9, 156.6, 147.7, 142.8, 141.1, 136.0, 135.43, 135.40, 129.4, 128.7, 128.4, 127.4, 125.7, 123.4, 122.8, 122.2, 121.1, 120.3, 118.1 (t, 1JC–F = 241.7 Hz), 109.2, 80.4, 72.0, 61.5 (dd, 2JC–F = 27.6, 21.5 Hz), 54.1, 45.4 (d, 3JC–F = 7.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.1 (d, J = 287.2 Hz, 1F), −122.4 (d, J = 287.2 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C27H20F2NO4S [M + H]+ 492.1076, found 492.1073.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(3-methoxyphenyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3fa). From 1f (26.4 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3fa (43.7 mg, 89% yield) was obtained as a white solid, m.p. 160–161 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 17.3 min (major), tR = 38.0 min (minor); 36% ee. [α]D25 = −117.5 (c = 1.1, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.83–7.80 (m, 2H, ArH), 7.72–7.63 (m, 3H, ArH), 7.45–7.41 (m, 1H, ArH), 7.23–7.19 (m, 1H, ArH), 7.02 (d, J = 8.8 Hz, 3H, ArH), 6.58 (d, J = 8.8 Hz, 2H, ArH), 6.23 (td, J1 = 56.8 Hz, J2 = 6.8 Hz, 1H, CF2H), 4.77 (d, J = 9.6 Hz, 1H, CH), 4.65–4.57 (m, 1H, CH), 3.62 (s, 3H, OCH3), 3.33 (s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.5, 198.9, 196.3, 159.0, 147.5, 142.6, 142.2, 136.23, 136.18, 135.8, 129.6, 129.1, 127.6, 125.9, 124.6, 123.5, 123.23, 123.18, 118.1 (t, 1JC–F = 242.1 Hz), 113.9, 81.3, 71.1, 62.4 (dd, 2JC–F = 27.0, 21.3 Hz), 55.0, 51.2 (d, 3JC–F = 7.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.0 (d, J = 288.4 Hz, 1F), −121.8 (d, J = 288.4 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C27H20F2NO4S [M + H]+ 492.1076, found 492.1081.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(4-fluorophenyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ga). From 1g (25.2 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ga (46.0 mg, 96% yield) as a white solid, m.p. 167–170 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 13.7 min (major), tR = 27.7 min (minor); 38% ee. [α]D25 = −186.0 (c = 0.23, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 7.6 Hz, 2H, ArH), 7.73–7.69 (m, 1H, ArH), 7.67–7.64 (m, 2H, ArH), 7.43 (t, J = 7.4 Hz, 1H, ArH), 7.21 (t, J = 7.6 Hz, 1H, ArH), 7.11–7.08 (m, 2H, ArH), 7.02 (d, J = 7.6 Hz, 1H, ArH), 6.75 (t, J = 8.4 Hz, 2H, ArH), 6.24 (td, J1 = 56.8 Hz, J2 = 6.8 Hz, 1H, CF2H), 4.81 (d, J = 10.0 Hz, 1H, CH), 4.67–4.58 (m, 1H, CH), 3.40 (br s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.3, 198.6, 196.0, 162.2 (1JC–F = 245.7 Hz), 147.4, 142.5, 142.1, 136.4, 136.3, 136.0, 130.1 (3JC–F = 8.1 Hz), 129.0, 128.7, 128.7, 127.6, 126.0, 123.6, 123.3 (4JC–F = 3.3 Hz), 118.1 (t, 1JC–F = 242.1 Hz), 115.5 (2JC–F = 21.3 Hz), 81.3, 70.9, 62.4 (dd, 2JC–F = 27.3, 21.6 Hz), 51.0 (d, 3JC–F = 7.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −113.8, −116.9 (d, J = 289.1 Hz, 1F), −121.8 (d, J = 289.1 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C26H17F3NO3S [M + H]+ 480.0876, found 480.0879.
(2S,4′S,5′S)-4′-(4-Chlorophenyl)-5′-(difluoromethyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ha). From 1h (26.8 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ha (49.0 mg, 98% yield) was obtained as a light-yellow solid, m.p. 123–127 °C. HPLC (Daicel Chiralpak IC column, mobile phase n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 9.4 min (minor), tR = 10.5 min (major); 24% ee. [α]D25 = −41.3 (c = 0.53, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.84–7.80 (m, 2H, ArH), 7.75–7.71 (m, 1H, ArH), 7.67 (d, J = 4.0 Hz, 2H, ArH), 7.43 (td, J1 = 7.6, J2 = 1.2 Hz, 1H, ArH), 7.21 (t, J = 7.5 Hz, 1H, ArH), 7.07–7.01 (m, 5H, ArH), 6.23 (td, J1 = 56.8 Hz, J2 = 6.8 Hz, 1H, CF2H), 4.80 (d, J = 9.6 Hz, 1H, CH), 4.66–4.58 (m, 1H, CH), 3.36 (br s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.2, 198.4, 195.9, 147.3, 142.4, 142.1, 136.4, 136.3, 136.1, 133.8, 131.5, 129.9, 128.9, 128.7, 127.6, 126.0, 123.5, 123.33, 123.27, 118.1 (t, 1JC–F = 242.1 Hz), 81.4, 70.7, 62.3 (dd, 2JC–F = 27.4, 21.6 Hz), 50.9 (d, 3JC–F = 7.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.0 (d, J = 289.1 Hz, 1F), −121.8 (d, J = 289.5 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C26H17ClF2NO3S [M + H]+ 496.0581, found 496.0578.
(2S,4′S,5′S)-4′-(4-Bromophenyl)-5′-(difluoromethyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ia). From 1i (31.2 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ia (47.4 mg, 88% yield) was obtained as a light-yellow solid, m.p. 185–187 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 19.4 min (major), tR = 39.3 min (minor); 41% ee. [α]D25 = −103.8 (c = 0.67, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.83 (t, J = 8.2 Hz, 2H, ArH), 7.76–7. 72 (m, 1H, ArH), 7.67 (d, J = 3.6 Hz, 2H, ArH), 7.43 (t, J = 7.6 Hz, 1H, ArH), 7.24–7.18 (m, 3H, ArH), 7.03–6.98 (m, 3H, ArH), 6.23 (td, J1 = 56.8 Hz, J2 = 6.8 Hz, 1H, CF2H), 4.78 (d, J = 9.6 Hz, 1H, CH), 4.66–4.57 (m, 1H, CH), 3.35 (br s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.3, 198.6, 196.0, 163.4, 160.9, 147.4, 142.5, 142.1, 136.4, 136.3, 136.0, 130.2, 130.1, 129.0, 127.6, 126.0, 123.6, 123.3, 123.2, 122.1, 118.1 (t, 1JC–F = 242.1 Hz), 115.6, 115.4, 81.3, 70.9, 62.4 (dd, 2JC–F = 27.2, 21.6 Hz), 50.9 (d, 3JC–F = 7.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.0 (d, J = 289.5 Hz, 1F), −121.8 (d, J = 289.5 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C26H1779BrF2NO3S [M + H]+ 540.0076, found 540.0062; calculated for C26H1781BrF2NO3S [M + H]+ 542.0055, found 542.0055.
(2S,4′S,5′S)-4′-(3-Bromophenyl)-5′-(difluoromethyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ja). From 1j (31.2 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ja (45.0 mg, 84% yield) as a light-yellow solid, m.p. 207–209 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 15.2 min (major), tR = 29.3 min (minor); 81% ee. [α]D25 = −47.6 (c = 0.58, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.83 (t, J = 6.4 Hz, 2H, ArH), 7.74–7.64 (m, 3H, ArH), 7.46–7.42 (m, 1H, ArH), 7.25 (s, 1H, ArH), 7.22 (t, J = 7.4 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 1H, ArH), 7.06 (d, J = 8.0 Hz, 1H, ArH), 7.03 (d, J = 8.0 Hz, 1H, ArH), 6.93 (t, J = 8.0 Hz, 1H, ArH), 6.24 (td, J1 = 56.8 Hz, J2 = 6.8 Hz, 1H, CF2H), 4.78 (d, J = 9.6 Hz, 1H, CH), 4.66–4.56 (m, 1H, CH), 3.37 (br s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.2, 198.3, 195.7, 147.4, 142.4, 142.0, 136.39, 136.35, 136.0, 135.3, 131.6, 131.2, 130.0, 129.0, 127.7, 127.2, 126.0, 123.5, 123.3, 122.5, 118.0 (t, 1JC–F = 242.2 Hz), 81.2, 70.8, 62.2 (dd, 2JC–F = 27.6, 21.8 Hz), 51.1 (d, 3JC–F = 7.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.1 (d, J = 289.1 Hz, 1F), −121.7 (d, J = 289.1 Hz, 1F) ppm. HRMS (ESI+): m/z caluclated for C26H1779BrF2NO3S [M + H]+ 540.0076, found 540.0063; calculated for C26H1781BrF2NO3S [M + H]+ 542.0055, found 542.0048.
(2S,4′S,5′S)-4′-(3,5-Dichlorophenyl)-5′-(difluoromethyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ka). From 1k (30.2 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ka (48.7 mg, 92% yield) was obtained as a light-yellow solid, m.p. 206–208 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 16.0 min (major), tR = 32.7 min (minor); 14% ee. [α]D25 = −24.2 (c = 0.48, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.0 Hz, 1H, ArH), 7.81 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H, ArH), 7.75–7.69 (m, 3H, ArH), 7.45 (td, J = 7.6, J2 = 1.2 Hz, 1H, ArH), 7.30 (d, J = 8.4 Hz, 1H, ArH), 7.25–7.21 (m, 1H, ArH), 7.11 (d, J = 2.0 Hz, 1H, ArH), 7.05 (dd, J = 8.6, 2.2 Hz, 2H, ArH), 6.29 (td, J1 = 56.8 Hz, J2 = 7.0 Hz, 1H, CF2H), 5.59 (d, J = 9.6 Hz, 1H, CH), 4.49–4.41 (m, 1H, CH), 3.29 (br s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.6, 198.7, 194.7, 147.4, 142.4, 141.8, 136.30, 136.28, 135.8, 134.1, 130.4, 129.8, 129.7, 129.1, 127.7, 127.1, 125.9, 123.52, 123.48, 123.2, 117.9 (t, 1JC–F = 242.2 Hz), 81.0, 71.0, 64.1 (dd, 2JC–F = 27.2, 21.4 Hz), 46.5 (d, 3JC–F = 7.8 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −116.8 (d, J = 289.9 Hz, 1F), −122.6 (d, J = 289.9 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C26H16Cl2F2NO3S [M + H]+ 530.0191, found 530.0191.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(4-nitrophenyl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3la). From 1l (27.9 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3la (45.6 mg, 90% yield) was obtained as a light yellow solid, m.p. 224–226 °C. HPLC (Daicel Chiralpak IC column, mobile phase n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 21.0 min (minor), tR = 27.4 min (major); 61% ee. [α]D25 = −1.01 (c = 1.38, CH2Cl2). 1H NMR (700 MHz, CDCl3): δ 7.95 (d, J = 9.1 Hz, 2H, ArH), 7.85–7.82 (m, 2H, ArH), 7.76–7.73 (m, 1H, ArH), 7.68 (d, J = 4.2 Hz, 2H, ArH), 7.45 (d, J = 7.4 Hz, 2H, ArH), 7.33 (d, J = 9.1 Hz, 2H, ArH), 7.23 (t, J = 7.7 Hz, 1H, ArH), 7.03 (d, J = 8.4 Hz, 1H, ArH), 6.26 (td, J1 = 56.7, J2 = 7.0 Hz, 1H, CF2H), 4.94 (d, J = 9.8 Hz, 1H, CH), 4.73–4.69 (m, 1H, CH), 3.41 (d, J = 7.7 Hz, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 199.9, 197.9, 195.4, 147.4, 147.2, 142.6, 142.3, 141.9, 140.7, 136.7, 136.5, 136.4, 134.2, 129.6, 128.8, 127.7, 126.1, 124.3, 123.64, 123.60, 123.4, 117.9 (t, 1JC–F = 242.2 Hz), 81.6, 70.4, 62.4 (dd, 2JC–F = 27.9, 22.1 Hz), 50.8 (d, 3JC–F = 7.7 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −116.9 (d, J = 290.5 Hz, 1F), −121.7 (d, J = 290.4 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C26H17F2N2O5S [M + H]+ 507.0821, found 507.0810.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(thiophen-2-yl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ma). From 1m (24.0 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3ma (41.1 mg, 88% yield) was obtained as a light-yellow solid, m.p. 208–210 °C. HPLC (Daicel Chiralpak IC column, mobile phase n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 12.4 min (minor), tR = 16.2 min (major); 81% ee. [α]D25 = −46.1 (c = 0.63, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 7.6 Hz, 1H, ArH), 7.82 (d, J = 7.6 Hz, 1H, ArH), 7.76–7.66 (m, 3H, ArH), 7.46–7.41 (m, 1H, ArH), 7.21 (t, J = 7.4 Hz, 1H, ArH), 7.03 (d, J = 7.6 Hz, 1H, ArH), 6.93 (d, J = 4.8 Hz, 1H, ArH), 6.80 (d, J = 3.4 Hz, 1H, ArH), 6.68 (dd, J1 = 5.0 Hz, J2 = 3.8 Hz, 1H, ArH), 6.24 (td, J1 = 56.6 Hz, J2 = 6.8 Hz, 1H, CF2H), 5.11 (d, J = 9.6 Hz, 1H, CH), 4.60–4.51 (m, 1H, CH), 3.37 (s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.3, 198.6, 195.7, 147.5, 142.8, 142.3, 136.4, 136.2, 135.9, 135.3, 128.9, 127.7, 127.1, 126.7, 126.0, 125.1, 123.6, 123.4, 123.3, 117.7 (t, 1JC–F = 242.3 Hz), 81.0, 70.6, 64.4 (dd, 2JC–F = 26.9, 21.6 Hz), 47.0 (d, 3JC–F = 7.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.5 (d, J = 289.1 Hz, 1F), −121.9 (d, J = 289.1 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C24H16F2NO3S2 [M + H]+ 468.0535, found 468.0526.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(furan-2-yl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3na). From 1n (22.4 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3na was obtained as a light-yellow solid, m.p. 216–218 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 14.0 min (major), tR = 41.9 min (minor); 11% ee. [α]D25 = −36.1 (c = 0.33, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.90–7.86 (m, 1H, ArH), 7.83–7.70 (m, 5H, ArH), 7.46–7.42 (m, 1H, ArH), 7.24–7.19 (m, 1H, ArH), 7.04 (d, J = 8.0 Hz, 1H, ArH), 6.93 (dd, J1 = 1.6, J2 = 0.8 Hz, 1H, ArH), 6.26 (dd, J1 = 56.8 Hz, J2 = 7.2 Hz, 1H, CF2H), 6.10 (d, J = 3.2 Hz, 1H, ArH), 6.03 (dd, J1 = 3.2 Hz, J2 = 2.0 Hz, 1H, ArH), 4.91 (d, J = 9.6 Hz, 1H, CH), 4.53–4.45 (m, 1H. CH), 3.39 (br s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ 200.3, 197.9, 195.4, 149.0, 147.6, 142.3, 136.3, 136.1, 135.8, 134.9, 129.3, 127.7, 125.9, 123.6, 123.4, 123.3, 122.9, 117.6 (t, 1JC–F = 241.9 Hz), 110.3, 108.9, 80.5, 69.3, 62.1 (dd, 2JC–F = 27.8, 22.2 Hz), 45.5 (d, 3JC–F = 7.9 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ −117.5 (d, J = 288.8 Hz, 1F), −122.0 (d, J = 288.8 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C24H16F2NO4S [M + H]+ 452.0763, found 452.0767.
(2S,4′S,5′S)-5′-(Difluoromethyl)-4′-(pyridin-2-yl)-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3oa). From 1o (23.5 mg, 0.10 mmol) and 2a (22.7 mg, 0.10 mmol), compound 3oa (43.9 mg, 95% yield) was obtained as a white solid, m.p. 207–210 °C. HPLC (Daicel Chiralpak ADH column, mobile phase n-hexane/2-propanol = 60:40, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 19.2 min (major), tR = 22.4 min (minor); 13% ee. [α]D25 = +13.0 (c = 0.71, CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (dd, J1 = 4.6 Hz, J2 = 1.0 Hz, 1H, ArH), 8.21 (d, J = 2.0 Hz, 1H, ArH), 7.90 (d, J = 7.6 Hz, 2H, ArH), 7.84–7.80 (m, 1H, ArH), 7.72 (d, J = 8.4 Hz, 2H, ArH), 7.58–7.53 (m, 2H, ArH), 7.32–7.25 (m, 2H, ArH), 7.18 (dd, J1 = 8.0 Hz, J2 = 4.8 Hz, 1H, ArH), 6.24 (td, J1 = 56.8 Hz, J2 = 5.8 Hz, 1H, CF2H), 5.15 (d, J = 5.6 Hz, 1H, CH), 4.69–4.50 (m, 2H, CH + NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ 200.2, 196.9, 195.8, 149.2, 149.1, 146.9, 141.5, 141.2, 137.6, 137.0, 136.7, 135.8, 129.1, 128.3, 126.8, 126.0, 123.9, 123.4, 123.2, 123.1, 118.2 (t, 1JC–F = 240.2 Hz), 82.7, 70.0, 60.9 (dd, 2JC–F = 26.8, 20.3 Hz), 54.8 ppm. 19F NMR (376 MHz, DMSO-d6): δ −115.6 (d, J = 285.8 Hz, 1F), −120.7 (d, J = 285.8 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C25H17F2N2O3S [M + H]+ 463.0923, found 463.0917.
(2S,4′S,5′S)-5′-(Difluoromethyl)-7-methyl-4′-phenyl-3H-dispiro[benzo[b]thiophene-2,2′-pyrrolidine-3′,2″-indene]-1″,3,3″-trione (3ab). From 1a (23.4 mg, 0.10 mmol) and 2b (24.1 mg, 0.10 mmol), compound 3ab (43.2 mg, 91% yield) was obtained as a white solid, m.p. 189-191 °C. HPLC (Daicel Chiralpak IC column, mobile phase n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection wavelength 254 nm): tR = 17.0 min (minor), tR = 24.4 min (major); 49% ee. [α]D25 = −155.8 (c = 1.18, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.6 Hz, 1H, ArH), 7.69–7.58 (m, 4H, ArH), 7.24 (s, 1H, ArH), 7.15 (d, J = 7.6 Hz, 1H, ArH), 7.12–7.08 (m, 2H, ArH), 7.06–6.97 (m, 3H, ArH), 6.25 (td, J1 = 56.8, J2 = 6.8 Hz, 1H, CF2H), 4.85 (d, J = 10.0 Hz, 1H, CH), 4.72–4.64 (m, 1H, CH), 3.39 (s, 1H, NH), 2.02 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 200.8, 198.8, 196.1, 147.1, 142.5, 142.1, 136.5, 136.0, 135.7, 132.8, 132.7, 128.9, 128.44, 128.41, 127.9, 126.0, 125.0, 123.2, 123.1, 118.1 (t, 1JC–F = 241.9 Hz), 81.2, 71.2, 62.2 (dd, 2JC–F = 27.2, 21.3 Hz), 52.0 (d, 3JC–F = 7.5 Hz), 18.4 ppm. 19F NMR (376 MHz, CDCl3): δ −117.1 (d, J = 288.0 Hz, 1F), −121.8 (d, J = 288.4 Hz, 1F) ppm. HRMS (ESI+): m/z calculated for C27H20F2NO3S [M + H]+ 476.1127, found 476.1125.

3.4. Procedure for the Scaled-Up Synthesis of Compound 3aa

In a dried bottle, 1a (0.468 g, 2.0 mmol), 2a (0.454 g, 2.0 mmol), chiral organocatalyst C9 (49.0 mg, 0.2 mmol, 20 mol%), and DCM (15.0 mL) were added. The mixture was stirred at room temperature for three days. After completion of the reaction, the residue was purified by flash column chromatography on silica gel to obtain the pure product 3aa (0.83 g, 90% yield, >20:1 dr, 91% ee).

4. Conclusions

In summary, we have successfully developed an asymmetric [3+2] cycloaddition strategy for N-2,2-difluoroethyl benzothiophenone imines and 2-arylidene-1,3-indanediones. Under mild conditions, a series of dispiro[benzothiophenone-indandione-pyrrolidine] compounds were obtained in 84–98% yields with 3–93% ee and 9:1–>20:1 dr. The scalability of this strategy for large-scale asymmetric synthesis of such dispiro[benzothiophenone- indanedione-pyrrolidine] derivatives was demonstrated through scale-up experiments, providing strong support for future practical applications and drug development.

Supplementary Materials

The following supplementary materials can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29204856/s1, spectroscopic data (1H and 13C NMR), chiral HPLC chromatograms for all new compounds 3, and X-ray crystal data for compound 3aa.

Author Contributions

H.-Y.L. performed the experiments, acquired, and analyzed the original data, and wrote the manuscript. D.-M.D. designed the research plan, supervised the experiments, modified all figures and schemes, analyzed, checked all the data, and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within this article and Supplementary Materials.

Acknowledgments

We thank the Analysis and Testing Center of Beijing Institute of Technology for the measurement of NMR and mass spectrometry.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 04856 g001
Figure 1. Medicines containing chiral spiroindanone skeletons.
Figure 1. Medicines containing chiral spiroindanone skeletons.
Molecules 29 04856 g001
Molecules 29 04856 g002
Figure 2. The reactive sites of 2-arylidene-1,3-indandione.
Figure 2. The reactive sites of 2-arylidene-1,3-indandione.
Molecules 29 04856 g002
Molecules 29 04856 sch001
Scheme 1. Previous reports and our current work. (a) [3+2] annulation by Du, et al. [16]; (b) [3+2] annulation by Zhou, et al. [17]; (c) [2+1] cycloaddition by Lei, et al. [18]; (d) our research plan.
Scheme 1. Previous reports and our current work. (a) [3+2] annulation by Du, et al. [16]; (b) [3+2] annulation by Zhou, et al. [17]; (c) [2+1] cycloaddition by Lei, et al. [18]; (d) our research plan.
Molecules 29 04856 sch001
Molecules 29 04856 g003
Figure 3. Organocatalysts selected.
Figure 3. Organocatalysts selected.
Molecules 29 04856 g003
Molecules 29 04856 sch002
Scheme 2. Substrate scope for dispiro[benzothiophenone-indandione-pyrrolidine]. 3. The reactions were carried out with 1 (0.10 mmol), 2 (0.10 mmol), and catalyst C9 (10 mol%) in DCM (2.0 mL) at room temperature for 24 h (48 h for 3ac and 3ad). Product yield was determined after purification on column chromatography. The dr values were determined by 1H NMR, and the ee values were determined by HPLC analysis.
Scheme 2. Substrate scope for dispiro[benzothiophenone-indandione-pyrrolidine]. 3. The reactions were carried out with 1 (0.10 mmol), 2 (0.10 mmol), and catalyst C9 (10 mol%) in DCM (2.0 mL) at room temperature for 24 h (48 h for 3ac and 3ad). Product yield was determined after purification on column chromatography. The dr values were determined by 1H NMR, and the ee values were determined by HPLC analysis.
Molecules 29 04856 sch002
Molecules 29 04856 sch003
Scheme 3. Scaled-up synthesis of 3aa.
Scheme 3. Scaled-up synthesis of 3aa.
Molecules 29 04856 sch003
Molecules 29 04856 g004
Figure 4. X-ray crystal structure of 3aa.
Figure 4. X-ray crystal structure of 3aa.
Molecules 29 04856 g004
Molecules 29 04856 sch004
Scheme 4. Proposed reaction mechanism.
Scheme 4. Proposed reaction mechanism.
Molecules 29 04856 sch004
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 29 04856 i001
EntrySolventCatalystTemperature
(°C)		Yield b (%)dr cee d (%)
1CH2Cl2C1rt80>20:176
2CH2Cl2C2rt75>20:176
3CH2Cl2C3rt92>20:162
4CH2Cl2C4rt68>20:154
5CH2Cl2C5rt86>20:145
6CH2Cl2C6rttrace––
7CH2Cl2C7rt82>20:139
8CH2Cl2C8rt90>20:150
9CH2Cl2C9rt95>20:192
10CH2Cl2C10rt87>20:181
11CH2Cl2C11rt83>20:160
12CHCl3C9rt85>20:141
13DCEC9rt86>20:172
14tolueneC9rt88>20:169
15MeCNC9rt89>20:157
16THFC9rt87>20:143
17MTBEC9rt75>20:127
18dioxaneC9rt89>20:161
19Et2OC9rt91>20:133
20 eCH2Cl2C9rt92>20:188
21 fCH2Cl2C9rt94>20:182
22CH2Cl2C9−1084>20:192
23CH2Cl2C94090>20:187
24 gCH2Cl2C9rtN.R.––
a Unless otherwise specified, the reactions were carried out with 1a (0.10 mmol), 2a (0.10 mmol), and catalyst (10 mol%) in solvent (2.0 mL) for 24 h. b Product yield was determined after purification on column chromatography. c Determined by 1H NMR analysis. d The enantiomeric excess (ee) was determined by HPLC analysis. e 15 mol% catalyst was used. f 5 mol% catalyst was used. g 10 mol% benzoic acid was added.
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Liu, H.-Y.; Du, D.-M. Organocatalyzed Enantioselective [3+2] Cycloaddition Reactions for Synthesis of Dispiro[benzothiophenone-indandione-pyrrolidine] Derivatives. Molecules 2024, 29, 4856. https://doi.org/10.3390/molecules29204856

AMA Style

Liu H-Y, Du D-M. Organocatalyzed Enantioselective [3+2] Cycloaddition Reactions for Synthesis of Dispiro[benzothiophenone-indandione-pyrrolidine] Derivatives. Molecules. 2024; 29(20):4856. https://doi.org/10.3390/molecules29204856

Chicago/Turabian Style

Liu, Hong-Yan, and Da-Ming Du. 2024. "Organocatalyzed Enantioselective [3+2] Cycloaddition Reactions for Synthesis of Dispiro[benzothiophenone-indandione-pyrrolidine] Derivatives" Molecules 29, no. 20: 4856. https://doi.org/10.3390/molecules29204856

APA Style

Liu, H. -Y., & Du, D. -M. (2024). Organocatalyzed Enantioselective [3+2] Cycloaddition Reactions for Synthesis of Dispiro[benzothiophenone-indandione-pyrrolidine] Derivatives. Molecules, 29(20), 4856. https://doi.org/10.3390/molecules29204856

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