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

Synthesis of Benzothiophene-Fused Pyran Derivatives via Piperidine Promoted Domino Reaction Hindawi Heteroatom Chemistry Volume 2019, Article ID 4361410, 6 pages https://doi.org/10.1155/2019/4361410 Research Article Synthesis of Benzothiophene-Fused Pyran Derivatives via Piperidine Promoted Domino Reaction Shihang Li, Aimin Yu, Jianfa Li , and Xiangtai Meng Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion, School of Chemistry & Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China Correspondence should be addressed to Jianfa Li; ljf 08@126.com and Xiangtai Meng; xtmeng@tjut.edu.cn Received 1 December 2018; Accepted 20 March 2019; Published 2 May 2019 Academic Editor: David Barker Copyright © 2019 Shihang Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A new domino reaction between thioaurones and malononitrile has been reported. is Th 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. 1. Introduction Many benzothiophene-fused heterocycles were synthesized (Scheme 2(a)) [18–22]. Herein, we will report another new Fused pyran ring existing in both numerous natural prod- domino reaction between thioaurone and malononitrile. To ucts and synthetic compounds is an important heteroatom our surprise, a series of benzothiophene-fused pyran deriva- framework [1–5], which demonstrate great function on tives were obtained (Scheme 2(b)). pharmacological activities, antibacterial, antiviral, anticoag- ulant, antianaphylactic, anticancer, diuretic activities, neu- 2. Materials and Methods rodegenerative disorders, and so on [6–10]. Recently, 2- aminochromenes are found to be employed as pigments, Material  was synthesized and reported in our previous work cosmetics, and agrochemicals [11–13]. Furthermore, the ther- [18, 19] and  was purchased from commercial access. apeutically effect on immune system diseases and dia- General synthetic procedure for  was as follows: betic complications entitled by substituted 2-amino-ben- under Ar atmosphere, to a solution of  (0.2 mmol) in zochromenes have been proved [14]. To date, there have dichloromethane (DCM) (2.0 mL)  (0.4 mmol) and piperi- been only limited methods to construct of a 2-amino-3- dine (10 mol%) were added and the mixture was stirred at cyan-pyranskeleton. Klimochkin’s group developed a con- room temperature for 2 h. After extraction with DCM, the venient one-step synthesis of 4-unsubstituted 2-amino-4H- organic layer was washed with saturated aqueous NaCl and chromene-2-carbonitriles from quaternary ammonium salts dried over MgSO and then concentrated under reduced (Scheme 1(a)) [15]. pressure. The residue was purified through flash column Subsequently, Takaki’s research group was given an effi- chromatography on silica gel (petroleum ether/ethyl acetate cient synthetic strategy for 2-amino-4H-chromenes from = 1:1 to 5:1) to ao ff rd the desired product . photochemical generated o-quinone methides and malonon- itrile (Scheme 1(b)) [16]. Aeft r that, Rao’s group also designed 3. Results and Discussion and synthesized a series of pyran derivatives in good yields by utilizing Baylis–Hillman chemistry (Scheme 1(c)) [17]. For eTh reaction between thioaurone a and malononitrile the past decades, there was a rapid development on the in dichloromethane as the solvent under reflux was first organic small molecule catalyzed domino reaction. During performed. Unfortunately, no product was detected by TLC our ongoing investigation of domino reactions, our research (Table 1, entry 1). Then piperidine was added as a catalyst group has developed many domino reactions on thioaurone. to promote the reaction. To our surprise, the reaction could 2 Heteroatom Chemistry O NH OH 2 DBU R R Malononitrile NMe I CN (a) OH O NH hv 1 1 R R Malononitrile CN R R Y = NMe , OH (b) NC CN 3 steps R CHO R = aromatic rings H N (c) Scheme 1: Previous methods to establish a 2-amino-3-cyan-pyran skeleton. #/ Et #/ Me [4+2] R ∘ THF, 67 C R ref. 19 S Ylide #/ Me #/ Et #/ Et R 2 MBH/PAr [4+3] P Ylide 3 Ar ref. 20 ref. 21 EtOH, 78 C R = o-PhX #/ Et ref. 22 X = OH, NHTs EtO C CO Me Domino CO Bn DEF/H O 2 S 178 C (a) NH H C 3 Catalyst CN H C NC CN Temp, Solvent COOEt COOEt 1a 2 3a (b) Scheme 2: Our works of domino reaction on thioaurone. give a quickly and cleanly conversion and the product was dropped to 57% (Table 1, entry 7). In the screening process, the additive effect of acetic acid was also screened. Insignif- obtained in a 70% yield (Table 1, entry 2). The structure icantly, there was no visible uc fl tuation on the yield (Table 1, of the product a was established by X-ray crystallography entry 8). As the reflux temperature provided a moderate yield, (Figure 1) [23]. Encouraged by this result, the solvent eeff ct the reaction was performed at room temperature (Table 1, was examined to optimize the reaction condition. There was entries 9-11). After attempting the above studies, the best only a feebly variation of the yield given by the different reaction condition is at room temperature using piperidine solvent such as chloroform, acetonitrile, tetrahydrofuran, as catalyst, and the yield up to 83% (entry 10). and ethyl alcohol; the reaction afforded the yields of 68%- With the best reaction conditions in hand, the substrate 73% aeft r stirring at the corresponding reu fl x temperature scope was examined with a series of thioaurone .Firstly, (Table 1, entries 3-6). When selecting toluene as the solvent, there was a negative effect on the conversion; the yield the ethyl ester on the R functional group switched to a Heteroatom Chemistry 3 Table 1: Optimization of condition . NH H C 3 Pyridine CN H C CN NC Temp, Solvent S COOEt COOEt 1a 2a 3a ∘ 𝑏 Entry Solvent Temp [ C] Time [min] Yield[%] 1 DCM 40 20 NR 2DCM 40 10 70 3CHCl 61 20 68 4THF 66 15 71 5CH CN 84 15 70 6EtOH 80 10 73 7 Toluene 110 20 57 8 EtOH 80 10 72 9EtOH r.t. 15 74 10 DCM r.t. 15 83 11 THF r.t. 10 63 Reaction conditions: 0.2 mol thioaurone a, 0.4 mol malononitrile a, 2.0 mL solvent at the corresponding temperature, and 10% mol piperidine as catalyst. 𝑏 𝑐 𝑑 Isolated yields. No catalyst. Acetic acid as an additive. Table 2: Scope of the domino reaction . NH O O CN piperidine 1 + 1 2 2 NC CN DCM, r.t. 2 R S 1 2a 3 1 2 𝑏 Entry R R Time [min] Yield[%] 15-CH (a)COOEt 15 83(a) 25-CH (b)COOBn 20 52(b) 35-CH (c) o-PhCl 10 84 (c) 45-CH (d) m-PhCl 10 99 (d) 55-CH (e) p-PhMe 15 69 (e) 65-F(f)COOEt 15 60(f) 75-Br(g)COOEt 20 59(g) 86-OMe(h)COOMe 15 71(h) 97-Cl(i)Phenyl 10 80(i) 𝑎 𝑏 Reaction conditions: 0.2 mol thioaurone , 0.4 mol malononitrile a,2.0 mL DCM atroom temperature,and 10% mol piperidine as the catalyst. Isolated yields. benzyl ester, leading to the desired product in yield of 52% (Table 2, entry 2). Subsequently, thioaurone  with aromatic groups on the  was also examined, for example, o- and m- chloro substituted c and d, p-methyl substituted e.And as aconsequence, the para 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 R was also studied. When using halogen atom to replace the methyl on the C5 position, the uo fl ro and bromo substituted substrates were given the corresponding products in 60% and 59% yields, respectively (Table 2, entries 6-7). Substrate h, Figure 1: X-ray crystal structure of a. bearing a 6-MeO group (R ), also worked well and furnished 4 Heteroatom Chemistry NH CO Et piperidine CO Et NC CH Cl , r.t., 8 h 2 2 CO Et S CO Et S 2 1a 2b 4, 63% Scheme 3: Domino reaction between a and b. −1 IR (KBr): 3411, 3332, 2362, 2336, 2192, 1719, 1653, 669 cm ; H NMR (400 MHz, CDCl )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, N𝐻 ), 4.62 (s, 1H, CH), 4.33 – 4.22 (m, 2H, OCH CH ), 2.46 (s, 3H, Ar-C𝐻 ), 1.34 (t, J =7.1 Hz, 3H, 2 3 3 OCH C𝐻 ) ppm; C NMR (100 MHz, CDCl )𝛿 =169.8 2 3 3 (COOEt), 160.8, 139.4, 134.8, 133.8, 129.0, 127.6, 122.4, 119.7, 119.1, 110.9, 62.3 (OCH CH ), 55.0 (CCN), 40.3 (CH), 21.4 2 3 (Ar-CH ), 14.2 (OCH CH ) ppm; ESI-HRMS [M+H] calcd. 3 2 3 for C H N O S 315.0798, found 315.0801. 16 15 2 3 Benzyl2-amino-3-cyano-8-methyl-4H-benzo[4,5]thieno[3,2- b]pyran-4-carboxylate (b). White solid, m.p. 177-179 C; IR (KBr): 3378, 3325, 3211, 2360, 2342, 2205, 1739, 1587, 1540, −1 1 734, 799 cm ; H NMR (400 MHz, CDCl )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, PhC𝐻 ), 4.90 (s, Figure 2: X-ray crystal structure of . 2H, N𝐻 ), 4.69 (s, 1H, CH), 2.45 (s, 3H, Ar-C𝐻 ) ppm; C 2 3 NMR (100 MHz, CDCl )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, the desired product in 71% yield. In addition, 7-Cl-substituted 110.7, 68.0 (OCH Bn), 54.9 (CCN), 40.3 (CH), 21.4 (Ar-CH ) 2 3 substrate i was also screened in this domino reaction. The ppm; ESI-HRMS [M+H] calcd. for C H N O S377.0954, 21 17 2 3 corresponding product i was obtained in yield of 80% found 377.0957. (Table 2, entry 9). In order to explore the domino reaction scope, ethyl 2-amino-4-(2-chlorophenyl)-8-methyl-4H-benzo[4,5]thieno[3, 2-cyanoacetate (b) was used in this domino reaction 2-b]pyran-3-carbonitrile (c). Red solid, m.p. 236-238 C; IR (Scheme 3). To our surprise, the corresponding product  was (KBr): 3482, 3321, 3284, 2360, 2200, 1650, 1581, 863, 800, 763, −1 1 obtained in yield of 63%. The structure of  was confirmed by 745 cm ; H NMR (400 MHz, CDCl )𝛿 =7.58 –7.50 (m, X-ray crystal structure analysis (Figure 2) [23]. 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, N𝐻 ), 2.47 (s, 3H, Ar-C𝐻 ) ppm; C NMR (100 MHz, 4. Conclusions 2 3 DMSO)𝛿 = 161.5, 140.9, 138.7, 135.0, 133.3, 132.4, 130.7, 130.3, In conclusion, a novel piperidine-catalyzed [4+2] domino 129.8, 129.2, 128.5, 127.8, 123.5, 120.4, 119.6, 117.0, 54.8 (CCN), reaction between thioaurone and malononitrile was devel- 37.4 (CH), 21.5 (Ar-CH ) ppm; ESI-HRMS [M+H] calcd. for oped. A number of benzothiophene ring fused 2-amino-3- C H N OSCl 353.0510, found 353.0515. 19 14 2 cyano-pyran derivatives were obtained in good yields. The 2-amino-4-(3-chlorophenyl)-8-methyl-4H-benzo[4,5]thieno[3, product structure was identified by NMR, HRMS, and X-ray crystal structure. 2-b]pyran-3-carbonitrile (d). White solid, m.p. 204-205 C; IR (KBr): 3470, 3322, 2360, 2342, 2199, 1661, 1581, 807, 799 −1 1 cm ; H NMR (400 MHz, CDCl )𝛿 =7.61 – 7.47 (m,2H, 5. Experimental 3 Ar-H), 7.28 (d, J =7.8 Hz,2H, Ar-H), 7.25 (s, 1H, Ar-H), 7.19 1 13 The H- and C-NMR spectrum were recorded at ambient (d, J =7.3 Hz, 2H, Ar-H), 4.93 (s, 1H, CH), 4.80 (s, 2H, N𝐻 ), temperature on Bruker 400 instruments. All spectra were 2.48 (s, 3H, Ar-C𝐻 ) ppm; C NMR (100 MHz, CDCl )𝛿 = 3 3 1 13 referenced to CDCl ( H𝛿 7.26 ppm and CNMR𝛿 77.00 159.8, 144.8, 138.4, 134.9, 133.8, 130.2, 129.2, 128.2, 127.8, 127.4, 1 13 ppm) and DMSO-d ( H𝛿 2.50 ppm and CNMR𝛿 39.52 125.9, 122.6, 119.8, 119.3, 117.3, 60.2 (CCN), 39.9 (CH), 21.5 (Ar-CH ) ppm; ESI-HRMS [M+H] calcd. for C H N OSCl ppm). HRMS were obtained on Waters Xevo Q-TOF MS 3 19 14 2 with ESI resource. Melting points were measured on a RY-I 353.0510, found 353.0513. apparatus and are reported to be uncorrected. 2-amino-8-methyl-4-(p-tolyl)-4H-benzo[4,5]thieno[3,2-b]pyran- Ethyl 2-amino-3-cyano-8-methyl-4H-benzo[4,5]thieno[3,2- 3-carbonitrile (e). White solid, m.p. 249-251 C; IR (KBr): ∘ −1 1 b]pyran-4-carboxylate (a). Yellow solid, m.p. 182-184 C; 3466, 3314, 2360, 2199, 1660, 1584, 1400, 872, 804 cm ; H Heteroatom Chemistry 5 −1 1 NMR (400 MHz, CDCl )𝛿 =7.57 – 7.48 (m, 2H, Ar-H), 7.21 3367, 3271, 2979, 2913, 1724, 1685, 1631, 804, 874 cm ; H –7.10(m, 5H, Ar-H), 4.92 (s, 1H, CH), 4.71 (s, 2H, N𝐻 ), 2.48 NMR (400MHz,CDCl )𝛿 =7.55 (d, J =8.4 Hz,1H, Ar-H), 2 3 (s, 3H, Ar-C𝐻 ), 2.32 (s, 3H, Ar-C𝐻 ) ppm; CNMR (100 7.38 (s, 1H, Ar-H), 7.12 (dd, J = 8.4, 2.0 Hz, 1H, Ar-H), 6.64 (br, 3 3 MHz, CDCl )𝛿 = 139.9, 138.1, 137.6, 134.7, 133.8, 129.6, 129.3, 2H, N𝐻 ), 4.78 (s, 1H, CH), 4.10-4.29 (m, 4H, 2× OCH CH ), 3 2 2 3 127.4, 127.1, 122.56 119.7, 119.5, 118.5, 61.2 (CCN), 39.7 (CH), 2.41 (s, 3H, Ar-C𝐻 ), 1.31 (t, J =7.2 Hz, 3H, OCH C𝐻 ), 3 2 3 21.5 (Ar-CH ), 21.1 (Ar-CH ) ppm; ESI-HRMS [M+H] calcd. 1.26 (t, J =7.2 Hz, 3H, OCH C𝐻 ) ppm; CNMR (100 3 3 2 3 for C H N OS 333.1056, found 333.1058. MHz, CDCl )𝛿 =172.2(COOEt), 169.0 (COOEt), 160.6, 139.1, 20 17 2 3 134.3, 133.5, 129.4, 127.0, 122.2, 119.5, 112.8, 72.8 (CCOOEt), 61.4 Ethyl 2-amino-3-cyano-8-fluoro-4H-benzo[4,5]thieno[3,2- (OCH CH ), 59.7 (OCH CH ), 40.4 (CH), 21.3 (Ar-CH ), 2 3 2 3 3 b]pyran-4-carboxylate (f ). Gray solid, m.p. 165-167 C; IR 14.3 (OCH CH ), 14.3 (OCH CH ) ppm; ESI-HRMS [M+H] 2 3 2 3 −1 calcd. for C H NO S 362.1057, found 362.1068. (KBr): 3424, 3372, 3327, 2198, 1739,1720, 1659, 1586, 854 cm ; 18 20 5 H NMR (400 MHz, CDCl )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 Data Availability Hz, 1H, Ar-H), 4.97 (s, 2H, N𝐻 ), 4.64 (s, 1H, CH), 4.36 – 4.21 (m, 2H, OCH CH ), 1.35 (t, J =7.1Hz,3H, OCH C𝐻 ) The copies of NMR spectra data used to support the findings 2 3 2 3 ppm; C NMR (100 MHz, CDCl )𝛿 =169.6 (COOEt), 160.8 of this study are included within the supplementary informa- (d, J = 242.3 Hz), 160.6, 139.3 (d, J = 4.3 Hz), 131.8 (d, J =1.7 tion lfi e(s) (available here). 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 (OCH CH ), 2 3 Conflicts of Interest 54.7 (CCN), 40.3 (CH), 14.2 (OCH CH ) ppm; ESI-HRMS 2 3 [M+H] calcd. for C H N O SF 319.0547, found 319.0551. 15 12 2 3 The authors declare that there are no conflicts of interest regarding the publication of this paper. Ethyl 2-amino-8-bromo-3-cyano-4H-benzo[4,5]thieno[3,2- b]pyran-4-carboxylate (g). Yellow solid, m.p. 195-197 C; IR Acknowledgments (KBr): 3460, 3366, 3314, 2194, 1740, 1720, 1652, 1583, 859, 874 −1 1 cm ; H NMR (400 MHz, CDCl )𝛿 =7.75 (s, 1H,Ar-H), 7.58 This work was financially supported by the National Natural (d, J =8.6Hz,1H,Ar-H), 7.45 (d, J=8.6Hz,1H,Ar-H), 4.99 (s, Science Foundation of China (Grant no. 21403154), the 2H, N𝐻 ), 4.64 (s, 1H, CH), 4.37 – 4.23 (m, 2H, OCH CH ), 2 2 3 Natural Science Foundation of Tianjin (Grant no. 13JCY- 1.36 (t, J =7.1 Hz, 3H, OCH C𝐻 ) ppm; C NMR (100 MHz, 2 3 BJC38700), and the Tianjin Municipal Education Commis- CDCl )𝛿 =169.5 (COOEt), 160.5, 138.8, 135.2, 130.2, 129.0, sion (Grants nos. 20120502, 20180KJ137). Xiangtai Meng 124.1, 122.6, 118.9, 112.8, 62.5 (OCH CH ), 54.9 (CCN), 40.2 2 3 is grateful for the support from the 131 Talents Program (CH), 14.2 (OCH CH ) ppm; ESI-HRMS [M+H] calcd. for 2 3 of Tianjin and Training Project of Innovation Team of C H N O SBr 378.9747, found 378.9751. 15 12 2 3 Colleges and Universities in Tianjin (TD13-5020). Shihang Li is grateful for the support from the National Innovation Methyl2-amino-3-cyano-7-methoxy-4H-benzo[4,5]thieno[3, Training Program of Undergraduates (no. 201710060149). 2-b]pyran-4-carboxylate (h). Red solid, m.p. 187-189 C; IR −1 (KBr): 3447, 3384, 3350, 2196, 1743, 1651, 1584, 848, 831 cm ; Supplementary Materials H NMR (400 MHz, CDCl )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 NMR spectra of all new compound (PDF) and crystallo- Hz, 1H, Ar-H), 4.90 (s, 2H, N𝐻 ), 4.61 (s, 1H, CH), 3.86 (s, graphic data for compound a and  (CIF). (Supplementary 3H, Ar-OC𝐻 ), 3.82 (s, 3H, COOC𝐻 ) ppm; CNMR (100 3 3 Materials) MHz, CDCl )𝛿 = 170.4 (COOCH ), 160.8, 158.6, 139.4, 138.3, 3 3 122.7, 120.5, 119.1, 114.9, 107.7, 105.4, 55.7 (COOCH ), 55.0 References (CCN), 53.0 (Ar-OCH ), 40.1 (CH) ppm; ESI-HRMS [M+H] calcd. for C H N O S 317.0591, found 317.0598. 15 13 2 4 [1] G. R. Pettit, Z. A. Cichacz, F. Gao et al., “Antineoplastic agents. 257. isolation and structure of spongistatin 1,” The Journal of 2-amino-6-chloro-4-phenyl-4H-benzo[4,5]thieno[3,2-b]pyran- Organic Chemistry, vol.58, no.6,pp.1302–1304, 1993. 3-carbonitrile (i). Yellow solid, m.p. 231-233 C; IR (KBr): −1 1 [2] A. B. Smith III, R. M. Corbett, G. R. 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[16] M.Fujiwara,M.Sakamoto,K. Komeyama,H. Yoshida, and K. Takaki, “Convenient Synthesis of 2-Amino-4H-chromenes from Photochemically Generated o-Quinone Methides and Malononitrile,” Journal of Heterocyclic Chemistry, vol.52,no.1, pp. 59–66, 2015. [17] T.N. Reddy, M.Ravinder,R. Bikshapathi,P.Sujitha, C.G. Kumar,and V.J. 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Synthesis of Benzothiophene-Fused Pyran Derivatives via Piperidine Promoted Domino Reaction

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Copyright © 2019 Shihang Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Heteroatom Chemistry Volume 2019, Article ID 4361410, 6 pages https://doi.org/10.1155/2019/4361410 Research Article Synthesis of Benzothiophene-Fused Pyran Derivatives via Piperidine Promoted Domino Reaction Shihang Li, Aimin Yu, Jianfa Li , and Xiangtai Meng Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion, School of Chemistry & Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China Correspondence should be addressed to Jianfa Li; ljf 08@126.com and Xiangtai Meng; xtmeng@tjut.edu.cn Received 1 December 2018; Accepted 20 March 2019; Published 2 May 2019 Academic Editor: David Barker Copyright © 2019 Shihang Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A new domino reaction between thioaurones and malononitrile has been reported. is Th 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. 1. Introduction Many benzothiophene-fused heterocycles were synthesized (Scheme 2(a)) [18–22]. Herein, we will report another new Fused pyran ring existing in both numerous natural prod- domino reaction between thioaurone and malononitrile. To ucts and synthetic compounds is an important heteroatom our surprise, a series of benzothiophene-fused pyran deriva- framework [1–5], which demonstrate great function on tives were obtained (Scheme 2(b)). pharmacological activities, antibacterial, antiviral, anticoag- ulant, antianaphylactic, anticancer, diuretic activities, neu- 2. Materials and Methods rodegenerative disorders, and so on [6–10]. Recently, 2- aminochromenes are found to be employed as pigments, Material  was synthesized and reported in our previous work cosmetics, and agrochemicals [11–13]. Furthermore, the ther- [18, 19] and  was purchased from commercial access. apeutically effect on immune system diseases and dia- General synthetic procedure for  was as follows: betic complications entitled by substituted 2-amino-ben- under Ar atmosphere, to a solution of  (0.2 mmol) in zochromenes have been proved [14]. To date, there have dichloromethane (DCM) (2.0 mL)  (0.4 mmol) and piperi- been only limited methods to construct of a 2-amino-3- dine (10 mol%) were added and the mixture was stirred at cyan-pyranskeleton. Klimochkin’s group developed a con- room temperature for 2 h. After extraction with DCM, the venient one-step synthesis of 4-unsubstituted 2-amino-4H- organic layer was washed with saturated aqueous NaCl and chromene-2-carbonitriles from quaternary ammonium salts dried over MgSO and then concentrated under reduced (Scheme 1(a)) [15]. pressure. The residue was purified through flash column Subsequently, Takaki’s research group was given an effi- chromatography on silica gel (petroleum ether/ethyl acetate cient synthetic strategy for 2-amino-4H-chromenes from = 1:1 to 5:1) to ao ff rd the desired product . photochemical generated o-quinone methides and malonon- itrile (Scheme 1(b)) [16]. Aeft r that, Rao’s group also designed 3. Results and Discussion and synthesized a series of pyran derivatives in good yields by utilizing Baylis–Hillman chemistry (Scheme 1(c)) [17]. For eTh reaction between thioaurone a and malononitrile the past decades, there was a rapid development on the in dichloromethane as the solvent under reflux was first organic small molecule catalyzed domino reaction. During performed. Unfortunately, no product was detected by TLC our ongoing investigation of domino reactions, our research (Table 1, entry 1). Then piperidine was added as a catalyst group has developed many domino reactions on thioaurone. to promote the reaction. To our surprise, the reaction could 2 Heteroatom Chemistry O NH OH 2 DBU R R Malononitrile NMe I CN (a) OH O NH hv 1 1 R R Malononitrile CN R R Y = NMe , OH (b) NC CN 3 steps R CHO R = aromatic rings H N (c) Scheme 1: Previous methods to establish a 2-amino-3-cyan-pyran skeleton. #/ Et #/ Me [4+2] R ∘ THF, 67 C R ref. 19 S Ylide #/ Me #/ Et #/ Et R 2 MBH/PAr [4+3] P Ylide 3 Ar ref. 20 ref. 21 EtOH, 78 C R = o-PhX #/ Et ref. 22 X = OH, NHTs EtO C CO Me Domino CO Bn DEF/H O 2 S 178 C (a) NH H C 3 Catalyst CN H C NC CN Temp, Solvent COOEt COOEt 1a 2 3a (b) Scheme 2: Our works of domino reaction on thioaurone. give a quickly and cleanly conversion and the product was dropped to 57% (Table 1, entry 7). In the screening process, the additive effect of acetic acid was also screened. Insignif- obtained in a 70% yield (Table 1, entry 2). The structure icantly, there was no visible uc fl tuation on the yield (Table 1, of the product a was established by X-ray crystallography entry 8). As the reflux temperature provided a moderate yield, (Figure 1) [23]. Encouraged by this result, the solvent eeff ct the reaction was performed at room temperature (Table 1, was examined to optimize the reaction condition. There was entries 9-11). After attempting the above studies, the best only a feebly variation of the yield given by the different reaction condition is at room temperature using piperidine solvent such as chloroform, acetonitrile, tetrahydrofuran, as catalyst, and the yield up to 83% (entry 10). and ethyl alcohol; the reaction afforded the yields of 68%- With the best reaction conditions in hand, the substrate 73% aeft r stirring at the corresponding reu fl x temperature scope was examined with a series of thioaurone .Firstly, (Table 1, entries 3-6). When selecting toluene as the solvent, there was a negative effect on the conversion; the yield the ethyl ester on the R functional group switched to a Heteroatom Chemistry 3 Table 1: Optimization of condition . NH H C 3 Pyridine CN H C CN NC Temp, Solvent S COOEt COOEt 1a 2a 3a ∘ 𝑏 Entry Solvent Temp [ C] Time [min] Yield[%] 1 DCM 40 20 NR 2DCM 40 10 70 3CHCl 61 20 68 4THF 66 15 71 5CH CN 84 15 70 6EtOH 80 10 73 7 Toluene 110 20 57 8 EtOH 80 10 72 9EtOH r.t. 15 74 10 DCM r.t. 15 83 11 THF r.t. 10 63 Reaction conditions: 0.2 mol thioaurone a, 0.4 mol malononitrile a, 2.0 mL solvent at the corresponding temperature, and 10% mol piperidine as catalyst. 𝑏 𝑐 𝑑 Isolated yields. No catalyst. Acetic acid as an additive. Table 2: Scope of the domino reaction . NH O O CN piperidine 1 + 1 2 2 NC CN DCM, r.t. 2 R S 1 2a 3 1 2 𝑏 Entry R R Time [min] Yield[%] 15-CH (a)COOEt 15 83(a) 25-CH (b)COOBn 20 52(b) 35-CH (c) o-PhCl 10 84 (c) 45-CH (d) m-PhCl 10 99 (d) 55-CH (e) p-PhMe 15 69 (e) 65-F(f)COOEt 15 60(f) 75-Br(g)COOEt 20 59(g) 86-OMe(h)COOMe 15 71(h) 97-Cl(i)Phenyl 10 80(i) 𝑎 𝑏 Reaction conditions: 0.2 mol thioaurone , 0.4 mol malononitrile a,2.0 mL DCM atroom temperature,and 10% mol piperidine as the catalyst. Isolated yields. benzyl ester, leading to the desired product in yield of 52% (Table 2, entry 2). Subsequently, thioaurone  with aromatic groups on the  was also examined, for example, o- and m- chloro substituted c and d, p-methyl substituted e.And as aconsequence, the para 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 R was also studied. When using halogen atom to replace the methyl on the C5 position, the uo fl ro and bromo substituted substrates were given the corresponding products in 60% and 59% yields, respectively (Table 2, entries 6-7). Substrate h, Figure 1: X-ray crystal structure of a. bearing a 6-MeO group (R ), also worked well and furnished 4 Heteroatom Chemistry NH CO Et piperidine CO Et NC CH Cl , r.t., 8 h 2 2 CO Et S CO Et S 2 1a 2b 4, 63% Scheme 3: Domino reaction between a and b. −1 IR (KBr): 3411, 3332, 2362, 2336, 2192, 1719, 1653, 669 cm ; H NMR (400 MHz, CDCl )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, N𝐻 ), 4.62 (s, 1H, CH), 4.33 – 4.22 (m, 2H, OCH CH ), 2.46 (s, 3H, Ar-C𝐻 ), 1.34 (t, J =7.1 Hz, 3H, 2 3 3 OCH C𝐻 ) ppm; C NMR (100 MHz, CDCl )𝛿 =169.8 2 3 3 (COOEt), 160.8, 139.4, 134.8, 133.8, 129.0, 127.6, 122.4, 119.7, 119.1, 110.9, 62.3 (OCH CH ), 55.0 (CCN), 40.3 (CH), 21.4 2 3 (Ar-CH ), 14.2 (OCH CH ) ppm; ESI-HRMS [M+H] calcd. 3 2 3 for C H N O S 315.0798, found 315.0801. 16 15 2 3 Benzyl2-amino-3-cyano-8-methyl-4H-benzo[4,5]thieno[3,2- b]pyran-4-carboxylate (b). White solid, m.p. 177-179 C; IR (KBr): 3378, 3325, 3211, 2360, 2342, 2205, 1739, 1587, 1540, −1 1 734, 799 cm ; H NMR (400 MHz, CDCl )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, PhC𝐻 ), 4.90 (s, Figure 2: X-ray crystal structure of . 2H, N𝐻 ), 4.69 (s, 1H, CH), 2.45 (s, 3H, Ar-C𝐻 ) ppm; C 2 3 NMR (100 MHz, CDCl )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, the desired product in 71% yield. In addition, 7-Cl-substituted 110.7, 68.0 (OCH Bn), 54.9 (CCN), 40.3 (CH), 21.4 (Ar-CH ) 2 3 substrate i was also screened in this domino reaction. The ppm; ESI-HRMS [M+H] calcd. for C H N O S377.0954, 21 17 2 3 corresponding product i was obtained in yield of 80% found 377.0957. (Table 2, entry 9). In order to explore the domino reaction scope, ethyl 2-amino-4-(2-chlorophenyl)-8-methyl-4H-benzo[4,5]thieno[3, 2-cyanoacetate (b) was used in this domino reaction 2-b]pyran-3-carbonitrile (c). Red solid, m.p. 236-238 C; IR (Scheme 3). To our surprise, the corresponding product  was (KBr): 3482, 3321, 3284, 2360, 2200, 1650, 1581, 863, 800, 763, −1 1 obtained in yield of 63%. The structure of  was confirmed by 745 cm ; H NMR (400 MHz, CDCl )𝛿 =7.58 –7.50 (m, X-ray crystal structure analysis (Figure 2) [23]. 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, N𝐻 ), 2.47 (s, 3H, Ar-C𝐻 ) ppm; C NMR (100 MHz, 4. Conclusions 2 3 DMSO)𝛿 = 161.5, 140.9, 138.7, 135.0, 133.3, 132.4, 130.7, 130.3, In conclusion, a novel piperidine-catalyzed [4+2] domino 129.8, 129.2, 128.5, 127.8, 123.5, 120.4, 119.6, 117.0, 54.8 (CCN), reaction between thioaurone and malononitrile was devel- 37.4 (CH), 21.5 (Ar-CH ) ppm; ESI-HRMS [M+H] calcd. for oped. A number of benzothiophene ring fused 2-amino-3- C H N OSCl 353.0510, found 353.0515. 19 14 2 cyano-pyran derivatives were obtained in good yields. The 2-amino-4-(3-chlorophenyl)-8-methyl-4H-benzo[4,5]thieno[3, product structure was identified by NMR, HRMS, and X-ray crystal structure. 2-b]pyran-3-carbonitrile (d). White solid, m.p. 204-205 C; IR (KBr): 3470, 3322, 2360, 2342, 2199, 1661, 1581, 807, 799 −1 1 cm ; H NMR (400 MHz, CDCl )𝛿 =7.61 – 7.47 (m,2H, 5. Experimental 3 Ar-H), 7.28 (d, J =7.8 Hz,2H, Ar-H), 7.25 (s, 1H, Ar-H), 7.19 1 13 The H- and C-NMR spectrum were recorded at ambient (d, J =7.3 Hz, 2H, Ar-H), 4.93 (s, 1H, CH), 4.80 (s, 2H, N𝐻 ), temperature on Bruker 400 instruments. All spectra were 2.48 (s, 3H, Ar-C𝐻 ) ppm; C NMR (100 MHz, CDCl )𝛿 = 3 3 1 13 referenced to CDCl ( H𝛿 7.26 ppm and CNMR𝛿 77.00 159.8, 144.8, 138.4, 134.9, 133.8, 130.2, 129.2, 128.2, 127.8, 127.4, 1 13 ppm) and DMSO-d ( H𝛿 2.50 ppm and CNMR𝛿 39.52 125.9, 122.6, 119.8, 119.3, 117.3, 60.2 (CCN), 39.9 (CH), 21.5 (Ar-CH ) ppm; ESI-HRMS [M+H] calcd. for C H N OSCl ppm). HRMS were obtained on Waters Xevo Q-TOF MS 3 19 14 2 with ESI resource. Melting points were measured on a RY-I 353.0510, found 353.0513. apparatus and are reported to be uncorrected. 2-amino-8-methyl-4-(p-tolyl)-4H-benzo[4,5]thieno[3,2-b]pyran- Ethyl 2-amino-3-cyano-8-methyl-4H-benzo[4,5]thieno[3,2- 3-carbonitrile (e). White solid, m.p. 249-251 C; IR (KBr): ∘ −1 1 b]pyran-4-carboxylate (a). Yellow solid, m.p. 182-184 C; 3466, 3314, 2360, 2199, 1660, 1584, 1400, 872, 804 cm ; H Heteroatom Chemistry 5 −1 1 NMR (400 MHz, CDCl )𝛿 =7.57 – 7.48 (m, 2H, Ar-H), 7.21 3367, 3271, 2979, 2913, 1724, 1685, 1631, 804, 874 cm ; H –7.10(m, 5H, Ar-H), 4.92 (s, 1H, CH), 4.71 (s, 2H, N𝐻 ), 2.48 NMR (400MHz,CDCl )𝛿 =7.55 (d, J =8.4 Hz,1H, Ar-H), 2 3 (s, 3H, Ar-C𝐻 ), 2.32 (s, 3H, Ar-C𝐻 ) ppm; CNMR (100 7.38 (s, 1H, Ar-H), 7.12 (dd, J = 8.4, 2.0 Hz, 1H, Ar-H), 6.64 (br, 3 3 MHz, CDCl )𝛿 = 139.9, 138.1, 137.6, 134.7, 133.8, 129.6, 129.3, 2H, N𝐻 ), 4.78 (s, 1H, CH), 4.10-4.29 (m, 4H, 2× OCH CH ), 3 2 2 3 127.4, 127.1, 122.56 119.7, 119.5, 118.5, 61.2 (CCN), 39.7 (CH), 2.41 (s, 3H, Ar-C𝐻 ), 1.31 (t, J =7.2 Hz, 3H, OCH C𝐻 ), 3 2 3 21.5 (Ar-CH ), 21.1 (Ar-CH ) ppm; ESI-HRMS [M+H] calcd. 1.26 (t, J =7.2 Hz, 3H, OCH C𝐻 ) ppm; CNMR (100 3 3 2 3 for C H N OS 333.1056, found 333.1058. MHz, CDCl )𝛿 =172.2(COOEt), 169.0 (COOEt), 160.6, 139.1, 20 17 2 3 134.3, 133.5, 129.4, 127.0, 122.2, 119.5, 112.8, 72.8 (CCOOEt), 61.4 Ethyl 2-amino-3-cyano-8-fluoro-4H-benzo[4,5]thieno[3,2- (OCH CH ), 59.7 (OCH CH ), 40.4 (CH), 21.3 (Ar-CH ), 2 3 2 3 3 b]pyran-4-carboxylate (f ). Gray solid, m.p. 165-167 C; IR 14.3 (OCH CH ), 14.3 (OCH CH ) ppm; ESI-HRMS [M+H] 2 3 2 3 −1 calcd. for C H NO S 362.1057, found 362.1068. (KBr): 3424, 3372, 3327, 2198, 1739,1720, 1659, 1586, 854 cm ; 18 20 5 H NMR (400 MHz, CDCl )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 Data Availability Hz, 1H, Ar-H), 4.97 (s, 2H, N𝐻 ), 4.64 (s, 1H, CH), 4.36 – 4.21 (m, 2H, OCH CH ), 1.35 (t, J =7.1Hz,3H, OCH C𝐻 ) The copies of NMR spectra data used to support the findings 2 3 2 3 ppm; C NMR (100 MHz, CDCl )𝛿 =169.6 (COOEt), 160.8 of this study are included within the supplementary informa- (d, J = 242.3 Hz), 160.6, 139.3 (d, J = 4.3 Hz), 131.8 (d, J =1.7 tion lfi e(s) (available here). 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 (OCH CH ), 2 3 Conflicts of Interest 54.7 (CCN), 40.3 (CH), 14.2 (OCH CH ) ppm; ESI-HRMS 2 3 [M+H] calcd. for C H N O SF 319.0547, found 319.0551. 15 12 2 3 The authors declare that there are no conflicts of interest regarding the publication of this paper. Ethyl 2-amino-8-bromo-3-cyano-4H-benzo[4,5]thieno[3,2- b]pyran-4-carboxylate (g). Yellow solid, m.p. 195-197 C; IR Acknowledgments (KBr): 3460, 3366, 3314, 2194, 1740, 1720, 1652, 1583, 859, 874 −1 1 cm ; H NMR (400 MHz, CDCl )𝛿 =7.75 (s, 1H,Ar-H), 7.58 This work was financially supported by the National Natural (d, J =8.6Hz,1H,Ar-H), 7.45 (d, J=8.6Hz,1H,Ar-H), 4.99 (s, Science Foundation of China (Grant no. 21403154), the 2H, N𝐻 ), 4.64 (s, 1H, CH), 4.37 – 4.23 (m, 2H, OCH CH ), 2 2 3 Natural Science Foundation of Tianjin (Grant no. 13JCY- 1.36 (t, J =7.1 Hz, 3H, OCH C𝐻 ) ppm; C NMR (100 MHz, 2 3 BJC38700), and the Tianjin Municipal Education Commis- CDCl )𝛿 =169.5 (COOEt), 160.5, 138.8, 135.2, 130.2, 129.0, sion (Grants nos. 20120502, 20180KJ137). Xiangtai Meng 124.1, 122.6, 118.9, 112.8, 62.5 (OCH CH ), 54.9 (CCN), 40.2 2 3 is grateful for the support from the 131 Talents Program (CH), 14.2 (OCH CH ) ppm; ESI-HRMS [M+H] calcd. for 2 3 of Tianjin and Training Project of Innovation Team of C H N O SBr 378.9747, found 378.9751. 15 12 2 3 Colleges and Universities in Tianjin (TD13-5020). Shihang Li is grateful for the support from the National Innovation Methyl2-amino-3-cyano-7-methoxy-4H-benzo[4,5]thieno[3, Training Program of Undergraduates (no. 201710060149). 2-b]pyran-4-carboxylate (h). Red solid, m.p. 187-189 C; IR −1 (KBr): 3447, 3384, 3350, 2196, 1743, 1651, 1584, 848, 831 cm ; Supplementary Materials H NMR (400 MHz, CDCl )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 NMR spectra of all new compound (PDF) and crystallo- Hz, 1H, Ar-H), 4.90 (s, 2H, N𝐻 ), 4.61 (s, 1H, CH), 3.86 (s, graphic data for compound a and  (CIF). (Supplementary 3H, Ar-OC𝐻 ), 3.82 (s, 3H, COOC𝐻 ) ppm; CNMR (100 3 3 Materials) MHz, CDCl )𝛿 = 170.4 (COOCH ), 160.8, 158.6, 139.4, 138.3, 3 3 122.7, 120.5, 119.1, 114.9, 107.7, 105.4, 55.7 (COOCH ), 55.0 References (CCN), 53.0 (Ar-OCH ), 40.1 (CH) ppm; ESI-HRMS [M+H] calcd. for C H N O S 317.0591, found 317.0598. 15 13 2 4 [1] G. R. Pettit, Z. A. Cichacz, F. Gao et al., “Antineoplastic agents. 257. isolation and structure of spongistatin 1,” The Journal of 2-amino-6-chloro-4-phenyl-4H-benzo[4,5]thieno[3,2-b]pyran- Organic Chemistry, vol.58, no.6,pp.1302–1304, 1993. 3-carbonitrile (i). Yellow solid, m.p. 231-233 C; IR (KBr): −1 1 [2] A. B. Smith III, R. M. Corbett, G. R. 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