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

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.


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).

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][28][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 R 2 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 (R 2 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 metabromo 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 (R 2 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 R 1 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-bromosubstituted 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][7][8][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].

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.

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 meltingpoint apparatus and were uncorrected. 1 H 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. 13 C 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 (CDCl 3 , 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. 1 H and 13 C 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.

Procedure for the Synthesis of Racemates of 3
To a dried small bottle were added 1 (0.04 mmol), 2 (0.03 mmol), Et 3 N (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.