# Synthesis of Benzothiophene-Fused Pyran Derivatives via Piperidine Promoted Domino Reaction

Authors: Shihang Li; Aimin Yu; Jianfa Li; Xiangtai Meng
Journal: Heteroatom Chemistry
 (2019)

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## Abstract

A new domino reaction between thioaurones and malononitrile has been reported. This reaction allows efficient access to benzothiophene-fused pyran derivatives in good yields under mild reaction conditions. The substrate scope is broad; a series of benzothiophene-fused pyran derivatives have been synthesized.


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## Body

## 1. Introduction

Fused pyran ring existing in both numerous natural products and synthetic compounds is an important heteroatom framework [1–5], which demonstrate great function on pharmacological activities, antibacterial, antiviral, anticoagulant, antianaphylactic, anticancer, diuretic activities, neurodegenerative disorders, and so on [6–10]. Recently, 2-aminochromenes are found to be employed as pigments, cosmetics, and agrochemicals [11–13]. Furthermore, the therapeutically effect on immune system diseases and diabetic complications entitled by substituted 2-amino-benzochromenes have been proved [14]. To date, there have been only limited methods to construct of a 2-amino-3-cyan-pyranskeleton. Klimochkin’s group developed a convenient one-step synthesis of 4-unsubstituted 2-amino-4H-chromene-2-carbonitriles from quaternary ammonium salts (Scheme 1(a)) [15].Scheme 1
Previous methods to establish a 2-amino-3-cyan-pyran skeleton.Subsequently, Takaki’s research group was given an efficient synthetic strategy for 2-amino-4H-chromenes from photochemical generatedo-quinone methides and malononitrile (Scheme 1(b)) [16]. After that, Rao’s group also designed and synthesized a series of pyran derivatives in good yields by utilizing Baylis–Hillman chemistry (Scheme 1(c)) [17]. For the past decades, there was a rapid development on the organic small molecule catalyzed domino reaction. During our ongoing investigation of domino reactions, our research group has developed many domino reactions on thioaurone. Many benzothiophene-fused heterocycles were synthesized (Scheme 2(a)) [18–22]. Herein, we will report another new domino reaction between thioaurone and malononitrile. To our surprise, a series of benzothiophene-fused pyran derivatives were obtained (Scheme 2(b)).Scheme 2
Our works of domino reaction on thioaurone.


## 2. Materials and Methods

Material1 was synthesized and reported in our previous work [18, 19] and2was purchased from commercial access.General synthetic procedure for3 was as follows: under Ar atmosphere, to a solution of1(0.2 mmol) in dichloromethane (DCM) (2.0 mL)2(0.4 mmol) and piperidine (10 mol%) were added and the mixture was stirred at room temperature for 2 h. After extraction with DCM, the organic layer was washed with saturated aqueous NaCl and dried over MgSO4 and then concentrated under reduced pressure. The residue was purified through flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1:1 to 5:1) to afford the desired product3.


## 3. Results and Discussion

The reaction between thioaurone1a and malononitrile2 in dichloromethane as the solvent under reflux was first performed. Unfortunately, no product was detected by TLC (Table 1, entry 1). Then piperidine was added as a catalyst to promote the reaction. To our surprise, the reaction could give a quickly and cleanly conversion and the product was obtained in a 70% yield (Table 1, entry 2). The structure of the product3a was established by X-ray crystallography (Figure 1) [23]. Encouraged by this result, the solvent effect was examined to optimize the reaction condition. There was only a feebly variation of the yield given by the different solvent such as chloroform, acetonitrile, tetrahydrofuran, and ethyl alcohol; the reaction afforded the yields of 68%-73% after stirring at the corresponding reflux temperature (Table 1, entries 3-6). When selecting toluene as the solvent, there was a negative effect on the conversion; the yield dropped to 57% (Table 1, entry 7). In the screening process, the additive effect of acetic acid was also screened. Insignificantly, there was no visible fluctuation on the yield (Table 1, entry 8). As the reflux temperature provided a moderate yield, the reaction was performed at room temperature (Table 1, entries 9-11). After attempting the above studies, the best reaction condition is at room temperature using piperidine as catalyst, and the yield up to 83% (entry 10).Table 1
Optimization ofconditiona.
Entry Solvent Temp [°C] Time [min] Yield%b  1 c DCM 40 20 NR 2 DCM 40 10 70 3 CHCl3 61 20 68 4 THF 66 15 71 5 CH3CN 84 15 70 6 EtOH 80 10 73 7 Toluene 110 20 57 8 d EtOH 80 10 72 9 EtOH r.t. 15 74 10 DCM r.t. 15 83 11 THF r.t. 10 63 R e a c t i o n   a conditions: 0.2 mol thioaurone 1a, 0.4 mol malononitrile 2a, 2.0 mL solvent at the corresponding temperature, and 10% mol piperidine as catalyst. Isolatedb yields. Noc catalyst. Aceticd acid as an additive.Figure 1
X-ray crystal structure of3a.With the best reaction conditions in hand, the substrate scope was examined with a series of thioaurone1. Firstly, the ethyl ester on the R2 functional group switched to a benzyl ester, leading to the desired product in yield of 52% (Table 2, entry 2). Subsequently, thioaurone1 with aromatic groups on the1 was also examined, for example, o- and m-chloro substituted1c and1d, p-methyl substituted1e. And as a consequence, thepara methyl-substituted substrate was not given an optimistic effect, but the other two were tolerated well and excellent; the yield was reached to 83% and 99%, respectively (Table 2, entries 3-5). Furthermore, the effect of R1 was also studied. When using halogen atom to replace the methyl on the C5 position, the fluoro and bromo substituted substrates were given the corresponding products in 60% and 59% yields, respectively (Table 2, entries 6-7). Substrate1h, bearing a 6-MeO group (R1), also worked well and furnished the desired product in 71% yield. In addition, 7-Cl-substituted substrate1i was also screened in this domino reaction. The corresponding product3i was obtained in yield of 80% (Table 2, entry 9).Table 2
Scope of the dominoreactiona.
Entry R1 R2 Time [min] Yield%b  1 5-CH3(1a) COOEt 15 83 (3a) 2 5-CH3(1b) COOBn 20 52 (3b) 3 5-CH3(1c) o-PhCl 10 84 (3c) 4 5-CH3(1d) m-PhCl 10 99 (3d) 5 5-CH3(1e) p-PhMe 15 69 (3e) 6 5-F(1f) COOEt 15 60 (3f) 7 5-Br(1g) COOEt 20 59 (3g) 8 6-OMe(1h) COOMe 15 71 (3h) 9 7-Cl(1i) Phenyl 10 80 (3i) R e a c t i o n   a conditions: 0.2 mol thioaurone 1, 0.4 mol malononitrile 2a, 2.0 mL DCM at room temperature, and 10% mol piperidine as the catalyst. Isolatedb yields.In order to explore the domino reaction scope, ethyl 2-cyanoacetate (2b) was used in this domino reaction (Scheme 3). To our surprise, the corresponding product4 was obtained in yield of 63%. The structure of4 was confirmed by X-ray crystal structure analysis (Figure 2) [23].Scheme 3
Domino reaction between1a and2b.Figure 2
X-ray crystal structure of4.


## 4. Conclusions

In conclusion, a novel piperidine-catalyzed[4+2] domino reaction between thioaurone and malononitrile was developed. A number of benzothiophene ring fused 2-amino-3-cyano-pyran derivatives were obtained in good yields. The product structure was identified by NMR, HRMS, and X-ray crystal structure.


## 5. Experimental

The1H- and 13C-NMR spectrum were recorded at ambient temperature on Bruker 400 instruments. All spectra were referenced to CDCl3 (1H δ 7.26 ppm and 13C NMR δ 77.00 ppm) and DMSO-d6 (1H δ 2.50 ppm and 13C NMR δ 39.52 ppm). HRMS were obtained on Waters Xevo Q-TOF MS with ESI resource. Melting points were measured on a RY-I apparatus and are reported to be uncorrected.Ethyl 2-amino-3-cyano-8-methyl-4H-benzo [4,5] thieno[3,2-b]pyran-4-carboxylate ( 3a ). Yellow solid, m.p. 182-184°C; IR (KBr): 3411, 3332, 2362, 2336, 2192, 1719, 1653, 669 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.60 (d,J = 8.3 Hz, 1H, Ar-H), 7.45 (s, 1H, Ar-H), 7.20 (d,J = 8.3 Hz, 1H, Ar-H), 4.91 (s, 2H, NH2), 4.62 (s, 1H, CH), 4.33 – 4.22 (m, 2H, OCH2CH3), 2.46 (s, 3H, Ar-CH3), 1.34 (t,J = 7.1 Hz, 3H, OCH2CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 169.8 (COOEt), 160.8, 139.4, 134.8, 133.8, 129.0, 127.6, 122.4, 119.7, 119.1, 110.9, 62.3 (OCH2CH3), 55.0 (CCN), 40.3 (CH), 21.4 (Ar-CH3), 14.2 (OCH2CH3) ppm; ESI-HRMS [M+H] calcd. for C16H15N2O3S 315.0798, found 315.0801.Benzyl2-amino-3-cyano-8-methyl-4H-benzo [4,5] thieno[3,2-b]pyran-4-carboxylate ( 3b ). White solid, m.p. 177-179°C; IR (KBr): 3378, 3325, 3211, 2360, 2342, 2205, 1739, 1587, 1540, 734, 799 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.60 (d,J = 8.3 Hz, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.37 (m, 5H, Ar-H), 7.20 (d,J = 8.3 Hz, 1H, Ar-H), 5.23 (s, 2H, PhCH2), 4.90 (s, 2H, NH2), 4.69 (s, 1H, CH), 2.45 (s, 3H, Ar-CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 169.7 (COOBn), 160.8, 139.4, 135.0, 134.8, 133.82, 129.0, 128.6, 128.5, 128.4, 127.7, 122.4, 119.7, 110.7, 68.0 (OCH2Bn), 54.9 (CCN), 40.3 (CH), 21.4 (Ar-CH3) ppm; ESI-HRMS [M+H] calcd. for C21H17N2O3S 377.0954, found 377.0957.2-amino-4-(2-chlorophenyl)-8-methyl-4H-benzo [4,5] thieno[3,2-b]pyran-3-carbonitrile ( 3c ). Red solid, m.p. 236-238°C; IR (KBr): 3482, 3321, 3284, 2360, 2200, 1650, 1581, 863, 800, 763, 745 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.58 – 7.50 (m, 2H, Ar-H), 7.40 (d,J = 8.3 Hz, 1H, Ar-H), 7.33 – 7.29 (m, 1H, Ar-H), 7.25 – 7.16 (m, 3H, Ar-H), 5.58 (s, 1H, CH), 4.79 (s, 2H, NH2), 2.47 (s, 3H, Ar-CH3) ppm; 13C NMR (100 MHz, DMSO) δ = 161.5, 140.9, 138.7, 135.0, 133.3, 132.4, 130.7, 130.3, 129.8, 129.2, 128.5, 127.8, 123.5, 120.4, 119.6, 117.0, 54.8 (CCN), 37.4 (CH), 21.5 (Ar-CH3) ppm; ESI-HRMS [M+H] calcd. for C19H14N2OSCl 353.0510, found 353.0515.2-amino-4-(3-chlorophenyl)-8-methyl-4H-benzo [4,5] thieno[3,2-b]pyran-3-carbonitrile ( 3d ). White solid, m.p. 204-205°C; IR (KBr): 3470, 3322, 2360, 2342, 2199, 1661, 1581, 807, 799 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.61 – 7.47 (m, 2H, Ar-H), 7.28 (d,J = 7.8 Hz, 2H, Ar-H), 7.25 (s, 1H, Ar-H), 7.19 (d,J = 7.3 Hz, 2H, Ar-H), 4.93 (s, 1H, CH), 4.80 (s, 2H, NH2), 2.48 (s, 3H, Ar-CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 159.8, 144.8, 138.4, 134.9, 133.8, 130.2, 129.2, 128.2, 127.8, 127.4, 125.9, 122.6, 119.8, 119.3, 117.3, 60.2 (CCN), 39.9 (CH), 21.5 (Ar-CH3) ppm; ESI-HRMS [M+H] calcd. for C19H14N2OSCl 353.0510, found 353.0513.2-amino-8-methyl-4-(p-tolyl)-4H-benzo [4,5] thieno[3,2-b]pyran-3-carbonitrile ( 3e ). White solid, m.p. 249-251°C; IR (KBr): 3466, 3314, 2360, 2199, 1660, 1584, 1400, 872, 804 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.57 – 7.48 (m, 2H, Ar-H), 7.21 – 7.10 (m, 5H, Ar-H), 4.92 (s, 1H, CH), 4.71 (s, 2H, NH2), 2.48 (s, 3H, Ar-CH3), 2.32 (s, 3H, Ar-CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 139.9, 138.1, 137.6, 134.7, 133.8, 129.6, 129.3, 127.4, 127.1, 122.56 119.7, 119.5, 118.5, 61.2 (CCN), 39.7 (CH), 21.5 (Ar-CH3), 21.1 (Ar-CH3) ppm; ESI-HRMS [M+H] calcd. for C20H17N2OS 333.1056, found 333.1058.Ethyl 2-amino-3-cyano-8-fluoro-4H-benzo [4,5] thieno[3,2-b]pyran-4-carboxylate ( 3f ). Gray solid, m.p. 165-167°C; IR (KBr): 3424, 3372, 3327, 2198, 1739,1720, 1659, 1586, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.66 (dd,J = 8.8, 4.5 Hz, 1H, Ar-H), 7.31 (dd,J = 8.7, 2.2 Hz, 1H, Ar-H), 7.13 (td,J = 8.8, 2.4 Hz, 1H, Ar-H), 4.97 (s, 2H, NH2), 4.64 (s, 1H, CH), 4.36 – 4.21 (m, 2H, OCH2CH3), 1.35 (t,J = 7.1 Hz, 3H, OCH2CH3) ppm; 13C NMR (100 MHz, CDCl3) δ =169.6 (COOEt), 160.8 (d,J = 242.3 Hz), 160.6, 139.3 (d,J = 4.3 Hz), 131.8 (d,J = 1.7 Hz), 129.7 (d,J = 9.8 Hz), 124.1 (d,J = 9.2 Hz), 118.9, 114.7 (d,J = 25.2 Hz), 113.3, 105.7 (d,J = 24.5 Hz), 62.5 (OCH2CH3), 54.7 (CCN), 40.3 (CH), 14.2 (OCH2CH3) ppm; ESI-HRMS [M+H] calcd. for C15H12N2O3SF 319.0547, found 319.0551.Ethyl 2-amino-8-bromo-3-cyano-4H-benzo [4,5] thieno[3,2-b]pyran-4-carboxylate ( 3g ). Yellow solid, m.p. 195-197°C; IR (KBr): 3460, 3366, 3314, 2194, 1740, 1720, 1652, 1583, 859, 874 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.75 (s, 1H, Ar-H), 7.58 (d,J = 8.6 Hz, 1H, Ar-H), 7.45 (d,J = 8.6 Hz, 1H, Ar-H), 4.99 (s, 2H, NH2), 4.64 (s, 1H, CH), 4.37 – 4.23 (m, 2H, OCH2CH3), 1.36 (t,J = 7.1 Hz, 3H, OCH2CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 169.5 (COOEt), 160.5, 138.8, 135.2, 130.2, 129.0, 124.1, 122.6, 118.9, 112.8, 62.5 (OCH2CH3), 54.9 (CCN), 40.2 (CH), 14.2 (OCH2CH3) ppm; ESI-HRMS [M+H] calcd. for C15H12N2O3SBr 378.9747, found 378.9751.Methyl2-amino-3-cyano-7-methoxy-4H-benzo [4,5] thieno[3,2-b]pyran-4-carboxylate ( 3h ). Red solid, m.p. 187-189°C; IR (KBr): 3447, 3384, 3350, 2196, 1743, 1651, 1584, 848, 831 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.54 (d,J = 8.8 Hz, 1H, Ar-H), 7.19 (d,J = 2.1 Hz, 1H, Ar-H), 7.00 (dd,J = 8.8, 2.1 Hz, 1H, Ar-H), 4.90 (s, 2H, NH2), 4.61 (s, 1H, CH), 3.86 (s, 3H, Ar-OCH3), 3.82 (s, 3H, COOCH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 170.4 (COOCH3), 160.8, 158.6, 139.4, 138.3, 122.7, 120.5, 119.1, 114.9, 107.7, 105.4, 55.7 (COOCH3), 55.0 (CCN), 53.0 (Ar-OCH3), 40.1 (CH) ppm; ESI-HRMS [M+H] calcd. for C15H13N2O4S 317.0591, found 317.0598.2-amino-6-chloro-4-phenyl-4H-benzo [4,5] thieno[3,2-b]pyran-3-carbonitrile ( 3i ). Yellow solid, m.p. 231-233°C; IR (KBr): 3345, 3314, 3282, 2205, 1647, 1584, 1172, 817, 784 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.64 (dd,J = 6.6, 2.2 Hz, 1H, Ar-H), 7.37 (m, 4H, Ar-H), 7.30 (m, 3H, Ar-H), 4.99 (s, 1H, CH), 4.78 (s, 2H, NH2) ppm; 13C NMR (100 MHz, CDCl3) δ = 159.5, 142.3, 138.6, 135.7, 130.6, 129.0, 128.4, 128.1, 127.6, 126.1, 125.2, 119.7, 119.1, 118.3, 60.9 (CCN), 40.1 (CH) ppm; ESI-HRMS [M+H] calcd. for C18H12N2OSCl 339.0353, found 339.0354.Diethyl 2-amino-8-methyl-4H-benzo [4,5] thieno[3,2-b]pyran-3,4-dicarboxylate ( 4 ). White solid, m.p. 139-141°C, IR (KBr): 3367, 3271, 2979, 2913, 1724, 1685, 1631, 804, 874 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.55 (d,J = 8.4 Hz, 1H, Ar-H), 7.38 (s, 1H, Ar-H), 7.12 (dd,J = 8.4, 2.0 Hz, 1H, Ar-H), 6.64 (br, 2H, NH2), 4.78 (s, 1H, CH), 4.10-4.29 (m, 4H, 2 × OCH2CH3), 2.41 (s, 3H, Ar-CH3), 1.31 (t,J = 7.2 Hz, 3H, OCH2CH3), 1.26 (t,J = 7.2 Hz, 3H, OCH2CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 172.2 (COOEt), 169.0 (COOEt), 160.6, 139.1, 134.3, 133.5, 129.4, 127.0, 122.2, 119.5, 112.8, 72.8 (CCOOEt), 61.4 (OCH2CH3), 59.7 (OCH2CH3), 40.4 (CH), 21.3 (Ar-CH3), 14.3 (OCH2CH3), 14.3 (OCH2CH3) ppm; ESI-HRMS [M+H] calcd. for C18H20NO5S 362.1057, found 362.1068.



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*Source: 4361410-2019-05-02.xml*