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Article

Asymmetric 1,4-Michael Addition Reaction of Azadienes with α-Thiocyanoindanones Catalyzed by Bifunctional Chiral Squaramide

by
Xiao-Yan Dong
and
Da-Ming Du
*
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(17), 5146; https://doi.org/10.3390/molecules26175146
Submission received: 3 August 2021 / Revised: 21 August 2021 / Accepted: 22 August 2021 / Published: 25 August 2021
(This article belongs to the Special Issue Asymmetric Catalysis and Synthesis 2023)
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Abstract

:
In this paper, the organocatalytic asymmetric 1,4-Michael addition reaction of azadienes and α-thiocyanoindanones was investigated. A series of chiral benzofuran compounds containing thiocyano group and quaternary carbon center were synthesized in moderate yields with good enantioselectivities (up to 90:10 er) and high diastereoselectivities (up to >95:5 dr). This is the first case of 1,4-Michael addition reaction using α-thiocyanoindanones to obtain a series of chiral thiocyano compounds and further broaden the scope of application of azadiene substrates. In addition, a possible reaction mechanism is also described in the article.

Graphical Abstract

1. Introduction

Benzofuran derivatives are an important class of heterocyclic compounds in many biologically active natural products [1,2,3,4]. Compounds containing benzofuran structural motifs exhibit excellent anticancer, antioxidation, and antifungal activities, and they can also be used as important structural motifs for some organic materials and drug molecules (Figure 1) [5,6,7,8]. The development of efficient and convenient ways to obtain compounds containing benzofuran structural motifs is the common goal pursued by many organic chemists. As far as we know, azadienes derived from benzofurans can undergo 1,4-Michael addition reactions with suitable nucleophiles due to their high reactivity to quickly construct multisubstituted benzofuran derivatives, and a variety of benzofuran derivatives have been successfully obtained by using azadienes [9,10,11,12,13,14].
In addition, thiocyanate compounds have various biological activities such as being anticancer, antimicrobial, and insecticidal; they have a wide range of applications in the fields of medicine, pesticides, and materials (Figure 2). Thiocyanate compounds are also important synthetic intermediates for obtaining sulfur-containing compounds [15,16,17,18,19,20]. Therefore, thiocyanate compounds have attracted the attention of more and more organic chemists. As far as we know, thiocyanate or trimethylsilyl alkyl isothiocyanates can react with substrates with leaving groups to obtain thiocyano compounds. Mainly include −SCN nucleophilic substitution reaction, +SCN electrophilic substitution reaction, and •SCN radical reaction. In addition, the reaction of cyanating reagents with sulfur-containing substrates is also an important method for obtaining thiocyanate compounds. Mainly include −CN nucleophilic substitution reaction, +CN electrophilic substitution reaction, and •CN radical reaction [21,22,23,24,25,26]. In recent years, the application research of thiocyanate compounds has also developed rapidly. However, in the development process, it also faces problems such as a low utilization rate of substrate atoms and poor economy [27,28]. α-Thiocyanoindanone is a nucleophile with a thiocyanato functional group; notably, by using α-thiocyanoindanone as a nucleophile, thiocyanate compounds can be obtained efficiently and conveniently. However, at present, the development of α-thiocyanoindanone in the asymmetric field is still relatively limited. To the best of our knowledge, there are few reports on the asymmetric catalytic reaction of α-thiocyanoindanones. In 2017, Yu and coworkers used α-thiocyanoindanones and α-aminosulfones to undergo a Mannich reaction, which obtained a series of optically active 2-thiocyanato-2-(1-aminoalkyl)-substituted 1-tetralones and 1-indanones (Scheme 1a) [29]. Regrettably, there has been no report about a series of optically active thiocyanate compounds by using α-thiocyanoindanone as a Michael donor to undergo a 1,4-addition asymmetric reaction.
Therefore, in this paper, we envisioned a 1,4-Michael addition reaction between azadienes and α-thiocyanoindanones, which could afford a series of optically active compounds containing benzofuran motif and thiocyano group with excellent diastereoselectivities and good enantioselectivities. This reaction not only provides a new strategy for the synthesis of thiocyanate compounds, but also the types of nucleophiles which react with azadienes are further expanded (Scheme 1b).

2. Results and Discussion

In the beginning, a series of organic catalysts were used to select the optimal catalyst for the 1,4-Michael addition reaction between azadienes and α-thiocyanoindanones. We first used a quinine-derived squaramide C1 to catalyze 1,4-Michael addition reaction of azadiene 1a and α-thiocyanoindanone 2a in dichloromethane solution. Fortunately, the target product 3aa was obtained with moderate yield and enantioselectivity (Table 1, entry 1). Encouraged by this result, several other catalysts C2–C9 (Figure 3) were screened to catalyze the 1,4-Michael addition reaction (Table 1, entries 2–9). However, no results better than C1 were obtained. Therefore, we still use C1 as the optimal catalyst.
Next, the influence of the solvent effect on the reaction was examined. A total of 14 solvents (Table 1, entries 10–23) was evaluated. Surprisingly, when ethyl acetate was used, although the product yield was lower than that using dichloromethane, the enantioselectivity and stereoselectivity were better than using dichloromethane. Therefore, ethyl acetate was chosen as the best solvent. After the optimal solvent was determined, we believed that temperature and catalyst loading may also have influence on the reaction outcome. As expected, when the catalyst loading was reduced to 2.5 mol%, although the enantioselectivity was increased to 86:14 er, the diastereoselectivity decreased to 89:11 dr (Table 1, entry 24). Considering that reducing the catalyst loading can increase the enantioselectivity, we decided to further reduce the catalyst loading to 1 mol%. Regrettably, both the er and dr values decreased (Table 1, entry 25). When the catalyst loading was increased to 10 mol%, the enantioselectivity increased to 87:13 er, and the diastereoselectivity decreased to 71:29 dr. (Table 1, entry 26); therefore, we decided to still use 5 mol% catalyst loading. We also tried to lower the temperature to 0, −10, and −20 °C (Table 1, entries 27–29). Fortunately, when the temperature was lowered to −10 °C, the er value could be increased to 90:10 er. In addition, we reduced the concentration of the reaction solution and put azadiene and α-thiocyanoindanone in 2 mL ethyl acetate. Compared with entry 28, the results showed that the yield, enantioselectivity, and diastereoselectivity decreased (Table 1, entry 30). Therefore, the best result was obtained using 0.05 mmol 1a, 0.04 mmol 2a, and 5 mol% C1 in EtOAc at −10 °C.
After the optimal reaction conditions were determined, the influence of different substituents on the substrates on the effect of this reaction was investigated. Firstly, the influence of different substituents in the azadienes 1 on the reaction was investigated, and the results are listed in Table 2 (entries 1–13). Regardless of whether R2 was an aromatic ring substituted with para-electron-withdrawing group or electron-donating group (Table 2, entries 2–7), the reaction of azadienes 1 with α-thiocyanoindanone 2a could basically maintain medium yields (58% to 87%), moderate to excellent diastereoselectivity (75:25 dr to >95:5 dr), and good enantioselectivities (79:21 er to 90:10 er).
When we used azadienes (R2 is a meta-substituted aromatic ring) for the reaction (Table 2, entries 8 and 9), the enantioselectivity, yield, and diastereoselectivity of the electron-withdrawing group decreased. By contrast, the electron-donating group could maintain the enantioselectivity, yield, and diastereoselectivity. It is considered that the meta-bromo substitution makes the solubility of azadiene in ethyl acetate worse, which leads to a worsening of the chiral control effect. We also investigated the influence of the azadiene (R2 is ortho-substituted aryl) on the reaction, which was affected by steric hindrance; it caused the reaction product to be only a trace amount. In addition, azadienes bearing 2-naphthyl, 2-thienyl, and 2-pyridinyl groups (Table 2, entries 10–12) also participated in the addition reaction to obtain corresponding products in good yields and er value. Finally, we also investigated azadiene when the R1 is methyl (Table 2, entries 13). Unfortunately, the enantioselectivity of this substrate has also decreased accordingly. Therefore, we found that the azadienes substituted by aryl groups at different positions have different control effects on the reaction. Generally speaking, the reaction has good universality for azadiene substrates.
In the next part, the effect of different substitutions of α-thiocyanoindanone on the reaction was further investigated. We mainly examined the 6-electron withdrawing/donating group and 5-electron withdrawing/donating group-substituted α-thiocyanoindanones. As shown in Table 3, entries 2–9, all the tried 5- and 6-substituted α-thiocyanoindanones can undergo 1,4-Michael addition with azadiene 1a to give the target products in moderate yields (43% to 66%). Among them, the electron-donating group substitution of α-thiocyanoindanone is significantly better than the electron-withdrawing group substitution. The 6-position except -OMe-substituted α-thiocyanindanone reacts with azadiene 1a to maintain excellent diastereoselectivity (>95:5 dr). The product obtained by the reaction of α-thiocyanoindanone substituted by the electron-donating group at the 6-position can maintain moderate yields and enantioselectivity (Table 3, entries 3 and 5). However, the enantioselectivities of the products decreased when the 6-fluoro- substituted and 6-bromo-substituted α-thiocyanoindanones reacted with azadiene 1a (Table 3, entries 2 and 4). The diastereoselectivities and enantioselectivities of the products obtained by reacting of 5-substituted α-thiocyanoindanones with azadiene 1a were all decreased (Table 3, entries 6–9). From this, we can see that different electron-withdrawing group substitutions of α-thiocyanoindanone generally result in poor reaction effects.
The structures of the products obtained by the reaction of azadienes and α-thiocyanoindanones were determined by NMR and HRMS. It is worth mentioning that because the enantioselectivity of 3ja is not very high (only 90:10 er) and cannot improve the enantioselectivity by recrystallization, we only obtained the relative configuration of the product through its single-crystal X-ray analysis (Figure 4) [30]. A similar phenomenon, only relative configuration, was provided owing to low enantioselectivity in Shi’s report [31].
Based on the experimental results and the relative configuration of 3ja, we proposed a possible reaction pathway for the catalytic asymmetric Michael addition (Scheme 2). The 2-thiocyano-1-indanone 2a is enolized and deprotonated via quinidine amine of chiral squaramide C1. Meanwhile, benzofuran-derived azadiene 1a is activated by catalyst C1 via forming hydrogen bonds. This dual activating mode of chiral squaramide C1 on the two substrates (transition state A) led to a stereoselective Michael addition to give an intermediate B. Then, an intramolecular protonation of the intermediate B occurs to finish the Michael addition and afford product 3aa with the observed relative configuration.

3. Conclusions

All in all, we have successfully established the 1,4-Michael addition reaction of azadienes and α-thiocyanoindanones catalyzed by a chiral bifunctional squaramide, and a series of optically active thiocyano compounds bearing both quaternary and tertiary double stereocenters were obtained. This reaction successfully constructs the thiocyano group into benzofuran derivatives under mild conditions, which provides a new strategy for the development and synthesis of chiral thiocyano compounds. Experimental details for the unsuccessful direct esterification of complex 7, the metathesis reactions and spectroscopic data can be found in the Supplementary Materials.

4. Materials and Methods

4.1. General Information

Commercially available compounds were used without further purification. Solvents were dried according to standard procedures. Column chromatography was performed with silica gel (200~300 mesh). Melting points were determined with an XT-4 melting-point apparatus and were uncorrected. 1H NMR spectra were measured with Bruker Ascend 400 MHz spectrometer; chemical shifts were reported in δ (ppm) units relative to tetramethylsilane (TMS) as internal standard. 13C NMR spectra were measured at 100 MHz with 400 MHz spectrometer; chemical shifts were reported in ppm relative to tetramethylsilane and referenced to solvent peak (CDCl3, δ C = 77.00). High-resolution mass spectra (Electron spray ionization) were measured with an Agilent 6520 Accurate-Mass Q-TOF MS system equipped with an electrospray ionization (ESI) source. Optical rotations were measured with a Krüss P8000 polarimeter at the indicated concentration with the units of g/100 mL. Enantiomeric excesses were determined by chiral HPLC analysis using an Agilent 1200 LC instrument with a Daicel Chiralpak IA, IC, or ADH column. 1H and 13C NMR spectra for newly synthesized compounds, X-ray single crystal data for product 3ja and copies of the HPLC chromatograms can be found in the Supplementary Materials.

4.2. Materials

1a‒1m were prepared according to the literature report [32,33]. 2a‒2i were prepared according to the literature [29]. The chiral organocatalysts were prepared by following the reported procedures [34,35,36,37].

4.3. Procedure for the Synthesis of Racemates of 3

To a dried small bottle were added 1 (0.04 mmol), 2 (0.03 mmol), Et3N (1.0 mg, 0.01 mmol, 0.2 equiv), and EtOAc (0.5 mL). After stirring at room temperature for 12 h, the reaction mixture was concentrated and directly purified by silica gel column chromatography to afford the racemates of 3.

4.4. Procedure for the Synthesis of Chiral Compounds 3

To a dried small bottle were added 1 (0.05 mmol), 2 (0.04 mmol), chiral organocatalyst C1 (1.3 mg, 0.002 mmol, and 0.05 equiv), and EtOAc (0.5 mL). The mixture was stirred at –10 °C; the reaction mixture was concentrated and directly purified by silica gel column chromatography to afford the desired products 3.
4-methyl-N-(2-((1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamide (3aa)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 16.0 mg (72% yield); m.p. 110–112 °C. HPLC (Daicel Chiralpak IA, n-hexane/ethyl acetate = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 19.0 min (minor), tR = 22.7 min (major); 90:10 er. [α]D25 = +69.1° (c 1.37, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 7.6 Hz, 1H, ArH), 7.72 (d, J = 8.0 Hz, 1H, ArH), 7.57−7.53 (m, 2H, ArH), 7.46 (d, J = 8.4 Hz, 2H, ArH), 7.41−7.30 (m, 4H, ArH), 7.09−7.02 (m, 5H, ArH), 6.86 (d, J = 8.4 Hz, 2H, ArH), 6.77 (s, 1H, NH), 5.05(s, 1H, CH), 4.01 (d, J = 19.2 Hz, 1H, CH2), 3.23 (d, J = 18.8 Hz, 1H, CH2), 2.21 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ198.4, 153.7, 151.4, 149.7, 143.5, 136.3, 135.9, 134.4, 133.0, 129.4, 129.3, 128.5, 128.4, 127.6, 127.0, 126.1, 125.9, 125.5, 125.4, 123.8, 121.0, 117.1, 111.4, 110.2, 61.7, 44.4, 35.8, 21.5 ppm. HRMS (ESI): m/z calcd. for C32H25N2O4S2 [M + H]+ 565.1250, found 565.1263.
N-(2-((4-bromophenyl)(1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3ba)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 17.5 mg (68% yield); m.p. 84–86 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 67.0 min (major), tR = 78.9 min (minor); 89:11 er. [α]D25 = +60° (c 0.32, CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.0 Hz, 1H, ArH), 7.70 (d, J = 7.6 Hz, 1H, ArH), 7.61−7.54 (m, 2H, ArH), 7.45 (d, J = 8.0 Hz, 2H, ArH), 7.40−7.29 (m, 4H, ArH), 7.16 (d, J = 8.4 Hz, 2H, ArH), 6.94–6.85 (m, 5H, ArH + NH), 5.07 (s, 1H, CH), 3.93 (d, J = 18.8 Hz, 1H, CH2), 3.23 (d, J = 18.8 Hz, 1H, CH2), 2.26 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.2, 153.7, 150.8, 149.5, 143.8, 136.5, 135.9, 133.6, 132.8, 131.6, 131.0, 129.3, 128.7, 127.1, 126.2, 125.7, 125.62, 125.60, 124.0, 122.0, 121.1, 117.4, 111.4, 110.0, 61.4, 43.7, 35.6, 21.6 ppm. HRMS (ESI): m/z calcd. for C32H2479BrN2O4S2 [M + H]+ 643.0355, found 643.0348. calcd. for C32H2481BrN2O4S2 [M + H]+ 645.0335, found 645.0332.
4-methyl-N-(2-((1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(p-tolyl)methyl)benzofuran-3-yl)benzenesulfonamide (3ca)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 20.1 mg (87% yield); m.p. 112–114 °C. HPLC (Daicel Chiralpak IA, n-hexane/ethyl acetate = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 41.6 min (minor), tR = 45.4 min (major); 90:10 er. [α]D25 = +84.7° (c 0.78, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 7.6 Hz, 1H, ArH), 7.71 (d, J = 7.2 Hz, 1H, ArH), 7.58−7.54 (m, 2H, ArH), 7.47 (d, J = 8.0 Hz, 2H, ArH), 7.40–7.29 (m, 4H, ArH), 6.91–6.82 (m, 6H, ArH), 6.68 (s, 1H, NH), 5.00 (s, 1H, CH), 4.00 (d, J = 18.8 Hz, 1H, CH2), 3.22 (d, J = 18.8 Hz, 1H, CH2), 2.21 (s, 3H, CH3), 2.19 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.4, 153.7, 151.7, 149.8, 143.5, 137.3, 136.2, 136.0, 133.0, 131.4, 129.3, 129.2, 129.1, 128.5, 127.1, 126.1, 126.0, 125.5, 125.4, 123.8, 121.0, 116.9, 111.3, 110.2, 61.7, 44.0, 35.8, 21.5, 21.0 ppm. HRMS (ESI): m/z calcd. for C33H27N2O4S2 [M + H]+ 579.1407, found 579.1403.
N-(2-((4-fluorophenyl)(1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3da)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 16.3 mg (70% yield); m.p. 108–110 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 28.5 min (major), tR = 35.2 min (minor); 88:12 er. [α]D25 = +115.7° (c 0.46, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.6 Hz, 1H, ArH), 7.68 (d, J = 8.0 Hz, 1H, ArH), 7.60−7.54 (m, 2H, ArH), 7.47 (d, J = 8.4 Hz, 2H, ArH), 7.41−7.29 (m, 4H, ArH), 7.06−7.03 (m, 2H, ArH), 6.90 (d, J = 8.0 Hz, 2H, ArH), 6.81 (s, 1H, NH), 6.75−6.71 (m, 2H, ArH), 5.08 (s, 1H, CH), 3.98 (d, J = 18.8 Hz, 1H, CH2), 3.23 (d, J = 18.8 Hz, 1H, CH2), 2.24 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.4, 161.9 (d, 1JC-F = 246.4 Hz), 153.7, 151.1, 149.6, 143.6, 136.5, 136.0, 132.9, 131.2 (d, 3JC-F = 8.1 Hz), 130.29, 130.26, 129.4, 128.7, 127.1, 126.1, 125.7, 125.6 (d, 4JC-F = 1.9 Hz), 123.9, 121.0, 117.1, 115.4 (d, 2JC-F = 21.3 Hz), 111.4, 110.1, 61.5, 43.6, 35.6, 21.4 ppm. HRMS (ESI): m/z calcd. for C32H24FN2O4S2 [M + H]+ 583.1156, found 583.1143.
N-(2-((4-chlorophenyl)(1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3ea)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 15.1 mg (63% yield), m.p. 114–116 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 65.4 min (major), tR = 75.7 min (minor); 88:12 er. [α]D25 = +60.6° (c 1.09, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.6 Hz, 1H, ArH), 7.70 (d, J = 7.6 Hz, 1H, ArH), 7.61–7.54 (m, 2H, ArH), 7.45 (d, J = 8.4 Hz, 2H, ArH), 7.42–7.37 (m, 2H, ArH), 7.35–7.30 (m, 2H, ArH), 7.03–6.97 (m, 4H, ArH), 6.88 (d, J = 8.0 Hz, 2H, ArH), 6.79 (s, 1H, NH), 5.07 (s, 1H, CH), 3.94 (d, J = 19.2 Hz, 1H, CH2), 3.22 (d, J = 18.8 Hz, 1H, CH2), 2.25 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.2, 153.8, 151.0, 149.5, 143.8, 136.5, 136.0, 133.8, 133.0, 132.8, 130.8, 129.3, 128.8, 128.6, 127.1, 126.2, 125.8, 125.7, 125.6, 124.0, 121.1, 117.3, 111.4, 110.0, 61.4, 43.6, 35.6, 21.5 ppm. HRMS (ESI): m/z calcd. for C32H24ClN2O4S2 [M + H]+ 599.0861, found 599.0859.
4-methyl-N-(2-((1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(4-(trifluoromethyl)phenyl)methyl)benzofuran-3-yl)benzenesulfonamide (3fa)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 15.7 mg (62% yield); m.p. 113–115 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 59.3 min (major), tR = 70.6 min (minor); 89:11 er. [α]D25 = +52.2° (c 0.48, CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 7.6 Hz, 1H, ArH), 7.64−7.55 (m, 3H, ArH), 7.47 (d, J = 8.4 Hz, 2H, ArH), 7.41−7.28 (m, 6H, ArH), 7.22 (d, J = 8.4 Hz, 2H, ArH), 6.94−6.87 (m, 3H, ArH + NH), 5.21 (s, 1H, CH), 3.93 (d, J = 19.2 Hz, 1H, CH2), 3.27 (d, J = 18.8 Hz, 1H, CH2), 2.21 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.0, 153.8, 150.8, 149.3, 143.7, 138.6, 136.6, 136.1, 132.8, 129.85 (q, 2JC-F = 32.3 Hz), 129.81, 129.4, 128.8, 127.1, 126.2, 125.77, 125.75, 125.71, 125.3 (q, 3JC-F = 3.7 Hz), 124.1, 123.7 (q, 1JC-F = 270.5 Hz), 120.9, 117.6, 111.4, 109.9, 61.6, 44.1, 35.7, 21.3 ppm. HRMS (ESI): m/z calcd. for C33H24F3N2O4S2 [M + H]+ 633.1124, found 633.1131.
4-methyl-N-(2-((1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(4-(oxo-l6-methyl)phenyl)methyl)benzofuran-3-yl)benzenesulfonamide (3ga)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 13.8 mg (58% yield); m.p. 105–107 °C. HPLC (Daicel Chiralpak IC, n-hexane/ethyl acetate = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 68.1 min (major), tR = 78.5 min (minor); 79:21 er. [α]D25 = +27.1° (c 0.51, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 7.6 Hz, 1H, ArH), 7.71 (d, J = 7.2 Hz, 1H, ArH), 7.58−7.53 (m, 2H, ArH), 7.48 (d, J = 8.4 Hz, 2H, ArH), 7.40−7.29 (m, 4H, ArH), 6.96−6.94 (m, 2H, ArH), 6.90 (d, J = 8.0 Hz, 2H, ArH ), 6.70 (s, 1H, NH), 6.58−6.54 (m, 2H, ArH), 5.00 (s, 1H, CH), 4.01 (d, J = 19.2 Hz, 1H, CH2), 3.68 (s, 3H, CH3), 3.22 (d, J = 19.2 Hz, 1H, CH2), 2.22 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.5, 158.8, 153.7, 151.7, 149.8, 143.5, 136.3, 136.0, 133.0, 130.6, 129.4, 128.5, 127.1, 126.4, 126.1, 126.0, 125.5, 125.4, 123.9, 121.0, 116.8, 113.7, 111.3, 110.2, 61.6, 55.0, 43.6, 35.8, 21.4 ppm. HRMS (ESI): m/z calcd. for C33H26N2O5S2Na [M + Na]+ 617.1175, found 617.1173.
4-methyl-N-(2-((1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(m-tolyl)methyl)benzofuran-3-yl)benzenesulfonamide (3ha)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 18.3 mg (79% yield); m.p. 102–104 °C. HPLC (Daicel Chiralpak IA, n-hexane/ethyl acetate = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 18.2 min (minor), tR = 20.2 min (major); 90:10 er. [α]D25 = +64.6° (c 0.50, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.6 Hz, 1H, ArH), 7.74 (d, J = 7.6 Hz, 1H, ArH), 7.57−7.54 (m, 2H, ArH), 7.47 (d, J = 8.4 Hz, 1H, ArH), 7.41−7.31 (m, 4H, ArH), 6.93−6.82 (m, 6H, ArH), 6.72 (s, 1H, NH), 5.02 (s, 1H, CH), 4.00 (d, J = 18.8 Hz, 1H, CH2), 3.23 (d, J = 19.2 Hz, 1H, CH2), 2.20 (s, 3H, CH3), 2.15 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.4, 153.7, 151.5, 149.8, 143.4, 138.0, 136.2, 136.0, 134.3, 133.1, 129.9, 129.3, 128.5, 128.4, 128.3, 127.1, 126.4, 126.1, 126.0, 125.5, 125.4, 123.9, 121.1, 117.0, 111.4, 110.2, 61.8, 44.3, 35.9, 21.49, 21.45. ppm. HRMS (ESI): m/z calcd. for C33H27N2O4S2 [M + H]+ 579.1407, found 579.1419.
N-(2-((3-bromophenyl)(1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3ia)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 14.9 mg (58% yield); m.p. 111–113 °C. HPLC (Daicel Chiralpak IA, n-hexane/ethyl acetate = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 35.0 min (minor), tR = 38.9 min (major); 63:37 er. [α]D25 = +51.0° (c 0.82, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.6 Hz, 1H, ArH), 7.73 (d, J = 7.6 Hz, 1H, ArH), 7.61−7.56 (m, 2H, ArH), 7.46 (d, J = 8.4 Hz, 2H, ArH), 7.43−7.31 (m, 4H, ArH), 7.23−7.18 (m, 2H, ArH), 7.01 (d, J = 8.0 Hz, 1H, ArH), 6.94−6.90 (m, 1H, ArH), 6.78 (s, 1H, NH), 5.01 (s, 1H, CH), 3.94 (d, J = 18.8 Hz, 1H, CH2), 3.23 (d, J = 19.2 Hz, 1H, CH2), 2.23 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.1, 153.8, 150.5, 149.5, 143.6, 136.7, 136.5, 135.8, 132.9, 132.1, 130.9, 129.9, 129.4, 128.7, 128.1, 127.1, 126.2, 125.68, 125.66, 124.0, 122.5, 121.1, 117.6, 111.5, 109.9, 61.6, 43.9, 35.7, 21.6 ppm. HRMS (ESI): m/z calcd. for C32H2479BrN2O4S2 [M + H]+ 643.0355, found 643.0354. calcd. for C32H2481BrN2O4S2 [M + H]+ 645.0335, found 64.0334.
4-methyl-N-(2-(naphthalen-1-yl(1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)methyl)benzofuran-3-yl)benzenesulfonamide (3ja)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 20.4 mg (83% yield); m.p. 118–120 °C. HPLC (Daicel Chiralpak IC, n-hexane/ethyl acetate = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 52.7 min (major), tR = 60.9 min (minor); 90:10 er. [α]D25 = +65.4° (c 0.41, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 7.6 Hz, 1H, ArH), 7.77 (d, J = 7.6 Hz, 1H, ArH), 7.70−7.61 (m, 3H, ArH), 7.52−7.29 (m, 10H, ArH), 7.25 (d, J = 7.2 Hz, 1H, ArH), 7.15 (d, J = 8.4 Hz, 1H, ArH), 6.87 (s, 1H, NH), 6.53 (d, J = 8.0 Hz, 2H, ArH), 5.25 (s, 1H, CH), 4.00 (d, J = 18.8 Hz, 1H, CH2), 3.24 (d, J = 19.2 Hz, 1H, CH2), 1.68 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.3, 153.9, 151.2, 149.5, 143.5, 136.3, 135.6, 132.9, 132.8, 132.3, 132.0, 129.1, 129.0, 128.6, 128.2, 128.1, 127.4, 126.9, 126.54, 126.51, 126.4, 126.1, 126.0, 125.6, 125.5, 123.9, 121.4, 117.3, 111.4, 110.3, 61.7, 44.1, 35.7, 20.8 ppm. HRMS (ESI): m/z calcd. for C36H26N2O4S2Na [M + Na]+ 637.1226, found 637.1228.
4-methyl-N-(2-((1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(thiophen-2-yl)methyl)benzofuran-3-yl)benzenesulfonamide (3ka)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 17.6 mg (76% yield); m.p. 110–112 °C. HPLC (Daicel Chiralpak IC, n-hexane/ethyl acetate = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 58.1 min (major), tR = 75.1 min (minor); 86:14 er. [α]D25 = +61.5° (c 1.03, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.6 Hz, 1H, ArH), 7.74 (d, J = 8.0 Hz, 1H, ArH), 7.60 (t, J = 7.6 Hz, 1H, ArH), 7.56−7.53 (m, 3H, ArH), 7.43−7.31 (m, 4H, ArH), 7.00 (dd, J1 = 5.0 Hz, J2 = 0.8 Hz, 1H, ArH), 6.95 (d, J = 8.0 Hz, 2H, ArH), 6.80 (s, 1H, NH), 6.68–6.66 (m, 1H, ArH), 6.47 (d, J = 3.6 Hz, 1H, ArH), 5.22 (s, 1H, CH), 4.05 (d, J = 18.8 Hz, 1H, CH2), 3.16 (d, J = 19.2 Hz, 1H, CH2), 2.24 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.1, 153.7, 150.3, 150.0, 143.6, 136.3, 136.0, 135.9, 133.0, 129.4, 128.7, 128.6, 127.1, 126.5, 126.3, 125.9, 125.8, 125.7, 125.6, 124.0, 121.0, 117.1, 111.5, 110.1, 77.3, 77.0, 76.7, 61.2, 40.5, 35.9, 21.6 ppm. HRMS (ESI): m/z calcd. for C30H23N2O4S3 [M + H]+ 571.0814, found 571.0818.
4-methyl-N-(2-((1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(pyridin-3-yl)methyl)benzofuran-3-yl)benzenesulfonamide (3la)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:2); 17.6 mg (78% yield); m.p. 104–106 °C. HPLC (Daicel Chiralpak ADH, n-hexane/2-propanol = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 76.7 min (major), tR = 106.2 min (minor); 86:14 er. [α]D25 = +35.3° (c 0.68, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.43–8.37 (m, 2H, ArH), 7.79 (d, J = 8.0 Hz, 1H, ArH), 7.60−7.53 (m, 3H, ArH), 7.46 (d, J = 8.4Hz, 3H, ArH), 7.40–7.34 (m, 3H, ArH), 7.25 (t, J = 7.6 Hz, 1H, ArH), 7.10–7.07 (m, 1H, ArH), 7.00–6.94 (m, 3H, ArH + NH), 5.20 (s, 1H, CH), 4.00 (d, J = 19.2 Hz, 1H, CH2), 3.29 (d, J = 19.2 Hz, 1H, CH2), 2.26 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 197.9, 153.8, 150.3, 149.3, 148.1, 143.9, 138.2, 136.7, 136.0, 132.8, 131.13, 132.11, 129.5, 128.9, 127.2, 126.2, 125.8, 125.7, 125.4, 124.0, 123.5, 120.5, 117.8, 111.5, 109.6, 61.6, 42.8, 35. 9, 21.5 ppm. HRMS (ESI): m/z calcd. for C31H24N3O4S2 [M + H]+ 566.1203, found 566.1207.
4-methyl-N-(5-methyl-2-((1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamide (3ma)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 13.9 mg (60% yield); m.p. 116–118 °C. HPLC (Daicel Chiralpak IC, n-hexane/ethyl acetate = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 20.9 min (minor), tR = 24.9 min (major); 72:28 er. [α]D25 = +51.8° (c 0.84, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.6 Hz, 1H, ArH), 7.54 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 7.48 (d, J = 8.4 Hz, 2H, ArH), 7.44−7.42 (m, 2H, ArH), 7.35 (t, J = 7.4 Hz, 1H, ArH), 7.30 (d, J = 8.0 Hz, 1H, ArH), 7.19 (dd, J1 = 8.6 Hz, J2 = 1.4 Hz, 1H, ArH), 7.09−7.00 (m, 5H, ArH), 6.87 (d, J = 8.0 Hz, 2H, ArH), 6.64 (s, 1H, NH), 5.01 (s, 1H, CH), 3.99 (d, J = 19.2 Hz, 1H, CH2), 3.21 (d, J = 19.2 Hz, 1H, CH2), 2.44 (s, 3H, CH3), 2.22 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.4, 152.2, 151.7, 149.7, 143.4, 136.2, 136.1, 134.5, 133.6, 133.0, 129.4, 129.3, 128.5, 128.4, 127.6, 127.1, 126.8, 126.1, 126.0, 125.5, 120.5, 116.8, 110.9, 110.2, 61.8, 44.4, 35.8, 21.5, 21.3 ppm. HRMS (ESI): m/z calcd. for C33H27N2O4S2 [M + H]+ 579.1407, found 579.1394.
N-(2-((6-fluoro-1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3ab)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 14.2 mg (61% yield); m.p. 94–96 °C. HPLC (Daicel Chiralpak IC, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 63.2 min (minor), tR = 80.0 min (major); 78:22 er. [α]D25 = +24.9° (c 0.36, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 7.6 Hz, 1H, ArH), 7.55 (d, J = 8.0 Hz, 1H, ArH), 7.46 (d, J = 8.0 Hz, 2H, ArH), 7.41−7.37 (m, 2H, ArH), 7.33−7.24 (m, 3H, ArH), 7.12−7.01 (m, 5H, ArH), 6.88 (d, J = 8.0 Hz, 2H, ArH), 6.71 (s, 1H, NH), 5.04 (s, 1H, CH), 4.00 (d, J = 18.8 Hz, 1H, CH2), 3.21 (d, J = 18.8 Hz, 1H, CH2), 2.22 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 197.7 (d, 4JC-F = 3.0 Hz), 162.6 (d, 1JC-F = 249.0 Hz), 153.7, 151.2, 145.2 (d, 4JC-F = 2.0 Hz), 143.5, 135.9, 134.8 (d, 3JC-F = 7.6 Hz), 134.2, 129.5, 129.3, 128.5, 127.8, 127.6 (d, 3JC-F = 8.0 Hz), 127.1, 125.8, 125.5, 124.1 (d, 2JC-F = 23.6 Hz), 123.9, 120.9, 117.2, 111.4, 111.1, 109.9, 62.4, 44.5, 35.4, 21.5 ppm. HRMS (ESI): m/z calcd. for C32H24FN2O4S2 [M + H]+ 583.1156, found 583.1161.
4-methyl-N-(2-((6-methyl-1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamide (3ac)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 15.3 mg (66% yield); m.p. 106–108 °C. HPLC (Daicel Chiralpak IC, n-hexane/ethyl acetate = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 9.2 min (minor), tR = 11.2 min (major); 87:13 er. [α]D25 = +100.7° (c 0.47, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.6 Hz, 1H, ArH), 7.55 (d, J = 8.4 Hz, 2H, ArH), 7.46 (d, J = 8.0 Hz, 2H, ArH), 7.41−7.30 (m, 3H, ArH), 7.19 (d, J = 8.0 Hz, 1H, ArH), 7.10−7.00 (m, 5H, ArH), 6.86 (d, J = 8.4 Hz, 2H, ArH), 6.70 (s, 1H, NH), 5.02 (s, 1H, CH), 3.94 (d, J = 18.8 Hz, 1H, CH2), 3.16 (d, J = 18.8 Hz, 1H, CH2), 2.35 (s, 3H, CH3), 2.21 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.4, 153.7, 151.5, 147.1, 143.4, 138.7, 137.6, 136.0, 134.5, 133.1, 129.43, 129.36, 128.4, 127.6, 127.0, 126.0, 125.8, 125.41, 125.38, 123.9, 121.0, 117.0, 111.3, 110.3, 62.0, 44.3, 35.5, 21.5, 21.0 ppm. HRMS (ESI): m/z calcd. for C33H27N2O4S2 [M + H]+ 579.1407, found 579.1396.
N-(2-((6-bromo-1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3ad)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 13.6 mg (53% yield); m.p. 198–200 °C. HPLC (Daicel Chiralpak IC, n-hexane/ethyl acetate = 80:20, flow rate 1.0 mL/min, detection at 254 nm): tR = 20.7 min (minor), tR = 22.9 min (major); 70:30 er. [α]D25 = +35.5° (c 0.45, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H, ArH), 7.69−7.63 (m, 2H, ArH), 7.54 (d, J = 8.0 Hz, 1H, ArH), 7.46 (d, J = 8.4 Hz, 1H, ArH), 7.39 (t, J = 7.8 Hz, 1H, ArH), 7.31(t, J = 7.6 Hz, 1H, ArH), 7.20 (d, J = 8.0 Hz, 1H, ArH), 7.13−7.00 (m, 5H, ArH), 6.88 (d, J = 8.0 Hz, 1H, ArH), 6.69 (s, 1H, NH), 5.04 (s, 1H, CH), 3.96 (d, J = 19.2 Hz, 1H, CH2), 3.19 (d, J = 19.2 Hz, 1H, CH2), 2.22 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 197.1, 153.7, 151.2, 148.3, 143.5, 139.1, 136.0, 134.8, 134.2, 129.5, 129.3, 128.6, 128.3, 127.8, 127.6, 127.1, 125.9, 125.5, 123.9, 122.7, 121.0, 117.2, 111.4, 109.8, 62.0, 44.4, 35.6, 21.5 ppm. HRMS (ESI): m/z calcd. for C32H2479BrN2O4S2 [M + H]+ 643.0355, found 643.0361; calcd. for C32H2481BrN2O4S2 [M + H]+ 645.0335, found 645.0345.
N-(2-((6-methyoxy-1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3ae)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 10.2 mg (43% yield); m.p. 118–120 °C. HPLC (Daicel Chiralpak IA, n-hexane/ethyl acetate = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 43.3 min (minor), tR = 67.2 min (major); 86:14 er. [α]D25 = +105.7° (c 1.46, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.0 Hz, 1H, ArH), 7.55 (d, J = 8.4 Hz, 1H, ArH), 7.47−7.45 (m, 2H, ArH), 7.38 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H, ArH), 7.32−7.29 (m, 1H, ArH), 7.207.17 (m, 2H, ArH), 7.14−7.01 (m, 6H, ArH), 6.85 (d, J = 8.0 Hz, 1H, ArH), 6.78 (s, 1H, NH), 5.05 (s, 1H, CH), 3.94 (d, J = 18.8 Hz, 1H, CH2), 3.80 (s, 3H, CH3), 3.14 (d, J = 18.4 Hz, 1H, CH2), 2.20 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 198.4, 160.0, 153.7, 151.4, 143.4, 142.6, 135.9, 134.4, 134.2, 129.4, 129.3, 128.4, 127.6, 127.0, 126.8, 125.9, 125.8, 125.4, 123.8, 121.0, 117.0, 111.3, 110.3, 106.3, 62.4, 55.6, 44.4, 35.2, 21.5 ppm. HRMS (ESI): m/z calcd. for C33H27N2O5S2 [M + H]+ 595.1356, found 595.1347.
N-(2-((5-fluoro-1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3af)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 10.5 mg (45% yield); m.p. 113–115 °C. HPLC (Daicel Chiralpak IA, n-hexane/ethyl acetate = 85:15, flow rate 1.0 mL/min, detection at 254 nm): tR = 42.1 min (minor), tR = 48.7min (major); 74:26 er. [α]D25 = +65.8° (c 1.2, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.78 (dd, J1 = 8.4 Hz, J2 = 5.2 Hz, 1H, ArH), 7.68 (d, J = 7.6 Hz, 1H, ArH), 7.55 (d, J = 8.4 Hz, 1H, ArH), 7.46 (d, J = 8.0 Hz, 2H, ArH), 7.39 (td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H, ArH), 7.32−7.29 (m, 1H, ArH), 7.11−7.02 (m, 6H, ArH), 6.87 (d, J = 8.0 Hz, 2H, ArH), 6.71 (s, 1H, NH), 5.05 (s, 1H, CH), 4.03 (d, J = 19.2 Hz, 1H, CH2), 3.25 (d, J = 19.2 Hz, 1H, CH2), 2.21 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 196.7, 167.9 (d, 1JC-F = 258.3 Hz), 153.7, 152.8 (d, 3JC-F = 10.6 Hz), 151.2, 143.5, 135.9, 134.2, 129.4, 129.3, 128.5, 128.0 (d, 3JC-F = 10.6 Hz), 127.8, 127.1, 125.8, 125.5, 123.9, 120.9, 117.2, 117.0, 113.0 (d, 2JC-F = 22.9 Hz), 111.4, 109.9, 62.0, 44.5, 35.9, 21.5 ppm. HRMS (ESI): m/z calcd. for C32H24FN2O4S2 [M + H]+ 583.1156, found 583.1148.
N-(2-((5-chloro-1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3ag)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 14.6 mg (61% yield); m.p. 128–130 °C. HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): tR = 42.9 min (minor), tR = 67.4 min (major); 62:38 er. [α]D25 = +24.0° (c 0.56, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.69 (t, J = 8.0 Hz, 2H, ArH), 7.55 (d, J = 8.0 Hz, 1H, ArH), 7.46 (d, J = 8.4 Hz, 2H, ArH), 7.41−7.37 (m, 1H, ArH), 7.34−7.30 (m, 3H, ArH), 7.12-7.00 (m, 6H, ArH), 6.87 (d, J = 8.0 Hz, 2H, ArH), 6.63 (s, 1H, NH), 5.04 (s, 1H, CH), 4.00 (d, J = 19.2 Hz, 1H, CH2), 3.21 (d, J = 19.2 Hz, 1H, CH2), 2.22 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 197.1, 153.7, 151.23, 151.15, 143.5, 143.0, 136.0, 134.2, 131.5, 129.5, 129.3, 128.6, 127.8, 127.1, 126.6, 126.4, 125.9, 125.5, 123.9, 121.0, 117.2, 111.4, 109.8, 61.8, 44.4, 35.6, 21.6 ppm. HRMS (ESI): m/z calcd. for C32H24ClN2O4S2 [M + H]+ 599.0861, found 599.0851.
N-(2-((5-bromo-1-oxo-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)-4-methylbenzenesulfonamide (3ah)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 16.5 mg (64% yield); m.p. 106–108 °C. HPLC (Daicel Chiralpak IA, n-hexane/ethyl acetate = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 26.7 min (minor), tR = 39.4 min (major); 69:31 er. [α]D25 = +44.8° (c 0.88, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 7.6 Hz, 1H, ArH), 7.62 (d, J = 8.4 Hz, 1H, ArH), 7.55 (d, J = 8.4 Hz, 1H, ArH), 7.50−7.45 (m, 4H, ArH), 7.39 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H, ArH), 7.33-7.29 (m, 1H, ArH), 7.12−7.01 (m, 5H, ArH), 6.87 (d, J = 8.4 Hz, 2H, ArH), 6.68 (s, 1H, NH), 5.05 (s, 1H, CH), 4.01 (d, J = 19.2 Hz, 1H, CH2), 3.22 (d, J = 18.8 Hz, 1H, CH2), 2.21 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 197.3, 153.7, 151.2, 151.1, 143.5, 135.9, 134.2, 132.3, 132.0 131.9, 129.4, 129.3, 128.6, 127.8, 127.1, 126.6, 125.8, 125.5, 123.9, 120.9, 117.2, 111.4, 109.8, 61.8, 44.4, 35.6, 21.5 ppm. HRMS (ESI): m/z calcd. for C32H2479BrN2O4S2 [M + H]+ 643.0355, found 643.0359; calcd. for C32H2481BrN2O4S2 [M + H]+ 645.0335, found 645.0342.
4-methyl-N-(2-((1-oxo-5-(oxo-l6-methyl)-2-thiocyanato-2,3-dihydro-1H-inden-2-yl)(phenyl)methyl)benzofuran-3-yl)benzenesulfonamide (3ai)
White solid; Flash column chromatography eluent (ethyl acetate/petroleum ether = 1:5); 15.2 mg (64% yield); m.p. 103–105 °C. HPLC (Daicel Chiralpak IA, n-hexane/ethyl acetate = 70:30, flow rate 1.0 mL/min, detection at 254 nm): tR = 10.1 min (minor), tR = 12.7 min (major); 85:15 er. [α]D25 = +78.6° (c 1.12, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 7.2 Hz, 1H, ArH), 7.68 (d, J = 8.4 Hz, 1H, ArH), 7.54 (d, J = 8.4 Hz, 1H, ArH), 7.46 (d, J = 8.4 Hz, 2H, ArH), 7.41−7.36 (m, 1H, ArH), 7.36−7.30 (m, 1H, ArH), 7.10−7.02 (m, 5H, ArH), 6.87−6.84 (m, 3H, ArH), 6.75−6.71 (m, 2H, ArH + NH), 5.00 (s, 1H, CH), 3.96 (d, J = 18.8 Hz, 1H, CH2), 3.81 (s, 3H, CH3), 3.19 (d, J = 18.8 Hz, 1H, CH2), 2.20 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 196.5, 166.5, 153.7, 153.0, 151.4, 143.4, 135.9, 134.5, 129.4, 129.3, 128.4, 127.6, 127.3, 127.0, 126.1, 126.0, 125.4, 123.8, 121.0, 117.1, 116.6, 111.3, 110.4, 109.3, 62.3, 55.7, 44.5, 35.9, 21.5 ppm. HRMS (ESI): m/z calcd. for C33H27N2O5S2 [M + H]+ 595.1356, found 595.1364.

Supplementary Materials

Spectroscopic data (1H and 13C NMR) and chiral HPLC chromatograms for all new compounds 3.

Author Contributions

X.-Y.D. performed the experiments, acquired and analyzed the original data, and wrote the preliminary manuscript. D.-M.D. conceived and designed the experiments, revised all figures and schemes, analyzed the data, and reviewed and edited 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

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 3 are available from the authors.

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Molecules 26 05146 g001 550
Figure 1. Selected biologically active benzofuran derivatives.
Figure 1. Selected biologically active benzofuran derivatives.
Molecules 26 05146 g001
Molecules 26 05146 g002 550
Figure 2. Selected biologically active molecules containing thiocyano group.
Figure 2. Selected biologically active molecules containing thiocyano group.
Molecules 26 05146 g002
Molecules 26 05146 sch001 550
Scheme 1. The asymmetric Mannich reaction of α-thiocyanoindanones and this work.
Scheme 1. The asymmetric Mannich reaction of α-thiocyanoindanones and this work.
Molecules 26 05146 sch001
Molecules 26 05146 g003 550
Figure 3. The screened organocatalysts.
Figure 3. The screened organocatalysts.
Molecules 26 05146 g003
Molecules 26 05146 g004 550
Figure 4. X-ray crystal structure of 3ja.
Figure 4. X-ray crystal structure of 3ja.
Molecules 26 05146 g004
Molecules 26 05146 sch002 550
Scheme 2. Proposed mechanism for the reaction.
Scheme 2. Proposed mechanism for the reaction.
Molecules 26 05146 sch002
Table
Table 1. Establishment of optimal reaction conditions for azadiene and α-thiocyanoindanone a.
Table 1. Establishment of optimal reaction conditions for azadiene and α-thiocyanoindanone a.
Molecules 26 05146 i001
EntrySolventCatalystYield b (%)dr cerd
1CH2Cl2C17790:1083:17
2CH2Cl2C25089:1180:20
3CH2Cl2C35486:1473:27
4CH2Cl2C46388:1276:24
5CH2Cl2C55386:1471:29
6CH2Cl2C62486:1467:33
7CH2Cl2C75393:781:19
8CH2Cl2C83584:1656:44
9CH2Cl2C94988:1267:33
10PhMeC188>95:581:19
11THFC156>95:582:18
12MTBEC145>95:578:22
13EtOAcC168>95:586:14
141,4-dioxaneC154>95:586:14
15PhCF3C182>95:580:20
16CHCl3C160>95:579:21
17PhClC167>95:582:18
18CH3CNC128>95:581:19
19acetoneC146>95:579:21
20ClCH2CH2ClC18376:2481:19
21CCl4C181>95:570:30
22dimethylbenzeneC13676:2463:37
23MeOHC124>95:545:55
24 eEtOAcC14189:1186:14
25 fEtOAcC13679:2163:37
26 gEtOAcC18071:2987:13
27 hEtOAcC15490:1086:14
28 iEtOAcC172>95:590:10
29 jEtOAcC18693:785:15
30 kEtOAcC14992:884:16
a Unless otherwise specified, reactions were carried out with 1a (0.05 mmol), 2a (0.04 mmol) and catalyst (5 mol%) in solvent (0.5 mL) at room temperature. b Isolated yield after column chromatography purification. c Determined by 1H NMR analysis. d Enantiometric ratio was determined by HPLC analysis. e 2.5 mol% catalyst was used. f 1 mol% catalyst was used. g 10 mol% catalyst was used. h The reaction was performed at 0 °C. i The reaction was performed at −10 °C. j The reaction was performed at −20 °C. k The reaction was carried out with 1a (0.05 mmol), 2a (0.04 mmol), and C1 (5 mol%) in EtOAc (2 mL) at −10 °C.
Table
Table 2. Substrate scope of azadienes a.
Table 2. Substrate scope of azadienes a.
Molecules 26 05146 i002
EntryR1/R2 (1)3Yield b (%)dr cer d
1H/Ph (1a)3aa72>95:590:10
2H/p-BrC6H4 (1b)3ba6880:2089:11
3H/p-MeC6H4 (1c)3ca87>95:590:10
4H/p-FC6H4 (1d)3da7085:1588:12
5H/p-ClC6H4 (1e)3ea6380:2088:12
6H/p-CF3C6H4 (1f)3fa6275:2589:11
7H/p-MeOC6H4 (1g)3ga58>95:579:21
8H/m-MeC6H4 (1h)3ha79>95:590:10
9H/m-BrC6H4 (1i)3ia5870:3063:37
10H/2-naphthyl (1j)3ja83>95:590:10
11H/2-thienyl (1k)3ka7686:1486:14
12H/2-pyridinyl (1l)3la78>95:586:14
13Me/Ph (1m)3ma60>95:572:28
a Unless otherwise noted, all reactions were carried out using 1 (0.05 mmol), 2a (0.04 mmol), and catalyst C1 (5 mol%) in solvent (0.5 mL) at −10 °C. b Isolated yield after column chromatography purification.c The dr values were determined by 1H NMR analysis. d Enantiometric ratio was determined by HPLC analysis.
Table
Table 3. Substrate scope of α-thiocyanoindanones a.
Table 3. Substrate scope of α-thiocyanoindanones a.
Molecules 26 05146 i003
EntryR3/R4 (2)3Yield b (%)dr cer d
1H/H (2a)3aa72>95:590:10
2F/H (2b)3ab61>95:578:22
3Me/H (2c)3ac66>95:587:13
4Br/H (2d)3ad53>95:570:30
5MeO/H(2e)3ae4387:1386:14
6H/F (2f)3af4586:1474:26
7H/Cl (2g)3ag6184:1662:38
8H/Br (2h)3ah6483:1769:31
9H/MeO (2i)3ai6483:1785:15
a Unless otherwise noted, all reactions were carried out using 1 (0.05 mmol), 2a (0.04 mmol), and catalyst C1 (5 mol%) in ethyl acetate (0.5 mL) at −10 °C. b Isolated yield after column chromatography purification. c The dr values were determined by 1H NMR analysis. d Enantiometric ratio was determined by HPLC analysis.
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Dong, X.-Y.; Du, D.-M. Asymmetric 1,4-Michael Addition Reaction of Azadienes with α-Thiocyanoindanones Catalyzed by Bifunctional Chiral Squaramide. Molecules 2021, 26, 5146. https://doi.org/10.3390/molecules26175146

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Dong X-Y, Du D-M. Asymmetric 1,4-Michael Addition Reaction of Azadienes with α-Thiocyanoindanones Catalyzed by Bifunctional Chiral Squaramide. Molecules. 2021; 26(17):5146. https://doi.org/10.3390/molecules26175146

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Dong, Xiao-Yan, and Da-Ming Du. 2021. "Asymmetric 1,4-Michael Addition Reaction of Azadienes with α-Thiocyanoindanones Catalyzed by Bifunctional Chiral Squaramide" Molecules 26, no. 17: 5146. https://doi.org/10.3390/molecules26175146

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