Heteroatom Chemistry
Volume 2019 (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.

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.

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 generated o-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

Material 1 was synthesized and reported in our previous work [18, 19] and 2 was purchased from commercial access.

General synthetic procedure for 3 was as follows: under Ar atmosphere, to a solution of 1 (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 product 3.

3. Results and Discussion

The reaction between thioaurone 1a and malononitrile 2 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 product 3a 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 of .

Entry
Solvent
Temp [°C]
Time [min]
Yield

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

EtOH
80
10
72

9
EtOH
r.t.
15
74

10
DCM
r.t.
15
83

11
THF
r.t.
10
63

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. yields. catalyst. acid as an additive.

Figure 1: X-ray crystal structure of 3a.

With the best reaction conditions in hand, the substrate scope was examined with a series of thioaurone 1. 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, thioaurone 1 with aromatic groups on the 1 was also examined, for example, o- and m-chloro substituted 1c and 1d, p-methyl substituted 1e. And as a consequence, 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 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). Substrate 1h, bearing a 6-MeO group (R¹), also worked well and furnished the desired product in 71% yield. In addition, 7-Cl-substituted substrate 1i was also screened in this domino reaction. The corresponding product 3i was obtained in yield of 80% (Table 2, entry 9).

Table 2: Scope of the domino .

Entry
R¹
R²
Time [min]
Yield

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)

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. 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 product 4 was obtained in yield of 63%. The structure of 4 was confirmed by X-ray crystal structure analysis (Figure 2) [23].

Scheme 3: Domino reaction between 1a and 2b.

Figure 2: X-ray crystal structure of 4.

4. Conclusions

In conclusion, a novel piperidine-catalyzed + 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

The ¹H- 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-benzothieno[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, N), 4.62 (s, 1H, CH), 4.33 – 4.22 (m, 2H, OCH₂CH₃), 2.46 (s, 3H, Ar-C), 1.34 (t, J = 7.1 Hz, 3H, OCH₂C) 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-benzothieno[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, PhC), 4.90 (s, 2H, N), 4.69 (s, 1H, CH), 2.45 (s, 3H, Ar-C) 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-benzothieno[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, N), 2.47 (s, 3H, Ar-C) 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-benzothieno[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, N), 2.48 (s, 3H, Ar-C) 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-benzothieno[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, N), 2.48 (s, 3H, Ar-C), 2.32 (s, 3H, Ar-C) 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-benzothieno[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, N), 4.64 (s, 1H, CH), 4.36 – 4.21 (m, 2H, OCH₂CH₃), 1.35 (t, J = 7.1 Hz, 3H, OCH₂C) 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-benzothieno[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, N), 4.64 (s, 1H, CH), 4.37 – 4.23 (m, 2H, OCH₂CH₃), 1.36 (t, J = 7.1 Hz, 3H, OCH₂C) 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-benzothieno[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, N), 4.61 (s, 1H, CH), 3.86 (s, 3H, Ar-OC), 3.82 (s, 3H, COOC) 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-benzothieno[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, N) 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-benzothieno[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, N), 4.78 (s, 1H, CH), 4.10-4.29 (m, 4H, 2 × OCH₂CH₃), 2.41 (s, 3H, Ar-C), 1.31 (t, J = 7.2 Hz, 3H, OCH₂C), 1.26 (t, J = 7.2 Hz, 3H, OCH₂C) 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.

Data Availability

The copies of NMR spectra data used to support the findings of this study are included within the supplementary information file(s) (available here).

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (Grant no. 21403154), the Natural Science Foundation of Tianjin (Grant no. 13JCYBJC38700), and the Tianjin Municipal Education Commission (Grants nos. 20120502, 20180KJ137). Xiangtai Meng is grateful for the support from the 131 Talents Program of Tianjin and Training Project of Innovation Team of Colleges and Universities in Tianjin (TD13-5020). Shihang Li is grateful for the support from the National Innovation Training Program of Undergraduates (no. 201710060149).

Supplementary Materials

NMR spectra of all new compound (PDF) and crystallographic data for compound 3a and 4 (CIF). (Supplementary Materials)

References

G. R. Pettit, Z. A. Cichacz, F. Gao et al., “Antineoplastic agents. 257. isolation and structure of spongistatin 1,” The Journal of Organic Chemistry, vol. 58, no. 6, pp. 1302–1304, 1993.

A. B. Smith III, R. M. Corbett, G. R. Pettit et al., “Synthesis and biological evaluation of a spongistatin ab-spiroketal analog,” Bioorganic & Medicinal Chemistry Letters, vol. 12, pp. 2039–2042, 2002.

P. W. Smith, S. L. Sollis, P. D. Howes et al., “Dihydropyrancarboxamides related to zanamivir:  a new series of inhibitors of influenza virus sialidases. 1. discovery, synthesis, biological activity, and structure−activity relationships of 4-Guanidino- and 4-Amino-4H-pyran-6-carboxamides,” Journal of Medicinal Chemistry, vol. 41, no. 6, pp. 787–797, 1998.

Z. P. Hu, W. J. Wang, X. G. Yin et al., “Enantioselective synthesis of 2-amino-4H-pyrans via the organocatalytic cascade reaction of malononitrile and α-substituted chalcones,” Tetrahedron: Asymmetry, vol. 23, no. 6-7, pp. 461–467, 2012.

S. Hatakeyama, N. Ochi, H. Numata, and S. Takano, “A new route to substituted 3-methoxycarbonyldihydropyrans; enantioselective synthesis of (–)-methyl elenolate,” Journal of the Chemical Society, Chemical Communications, vol. 1988, no. 17, pp. 1202–1204, 1988.

D. Kumar, V. B. Reddy, S. Sharad, U. Dude, and S. Kapur, “A facile one-pot green synthesis and antibacterial activity of 2-amino-4H-pyrans and 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromenes,” European Journal of Medicinal Chemistry, vol. 44, no. 9, pp. 3805–3809, 2009.

P. G. Wyatt, B. A. Coomber, D. N. Evans et al., “Sialidase inhibitors related to zanamivir. further SAR studies of 4-amino-4H-pyran-2-carboxylic acid-6-propylamides,” Bioorganic & Medicinal Chemistry Letters, vol. 11, no. 5, pp. 699–673, 2001.

W. Kemnitzer, J. Drewe, S. Jiang et al., “Discovery of 4-Aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay. 4. structure–activity relationships of N-Alkyl substituted pyrrole fused at the 7,8-positions,” Journal of Medicinal Chemistry, vol. 51, no. 3, pp. 417–423, 2008.

L. Bonsignore, G. Loy, D. Secci, and A. Calignano, “Synthesis and pharmacological activity of 2-oxo-(2H) 1-benzopyran-3-carboxamide derivatives,” European Journal of Medicinal Chemistry, vol. 28, no. 6, pp. 517–520, 1993.

H. Gourdeau, L. Leblond, B. Hamelin et al., “Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents,” Molecular Cancer Therapeutics, vol. 3, no. 11, pp. 1375–1384, 2004.

N. M. Sabry, H. M. Mohamed, E. S. A. E. H. Khattab et al., “Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activitie,” European Journal of Medicinal Chemistry, vol. 46, no. 2, pp. 765–772, 2011.

Q. Ren, W.-Y. Siau, Z. Du, K. Zhang, and J. Wang, “Expeditious assembly of a 2-Amino-4H-chromene skeleton by using an enantioselective Mannich intramolecular ring cyclization-tautomerization cascade sequence,” Chemistry - A European Journal, vol. 17, no. 28, pp. 7781–7785, 2011.

W. Kemnitzer, Drewe, S. Jiang et al., “Discovery of 4-Aryl-4H-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-based High-Throughput Screening Assay. 1. Structure−Activity Relationships of the 4-Aryl Group,” Journal of Medicinal Chemistry, vol. 47, no. 25, pp. 6299–6310, 2004.

S. J. Ambler, W. F. Heath, and J. P. Singh, “Chemical abstracts,” Eur. Patent, vol. 122, Article ID 31327, 619314, 1995.

V. A. Osyanin, D. V. Osipov, and Y. N. Klimochkin, “Convenient one-step synthesis of 4-unsubstituted 2-amino-4H-chromene-2-carbonitriles and 5-unsubstituted 5H-chromeno[2,3-b]pyridine-3-carbonitriles from quaternary ammonium salts,” Tetrahedron, vol. 68, no. 27-28, pp. 5612–5618, 2012.

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.

T. N. Reddy, M. Ravinder, R. Bikshapathi, P. Sujitha, C. G. Kumar, and V. J. Rao, “Design, synthesis, and biological evaluation of 4-H pyran derivatives as antimicrobial and anticancer agents,” Medicinal Chemistry Research, vol. 26, no. 11, pp. 2832–2844, 2017.

Y. Zhang, A. Yu, J. Jia et al., “NaH promoted [4+3] annulation of crotonate-derived sulfur ylides with thioaurones: synthesis of 2,5-dihydrobenzo[4,5]thieno[3,2-b]oxepines,” Chemical Communications, vol. 53, no. 77, pp. 10672–10675, 2017.

J. Jia, A. Yu, S. Ma, Y. Zhang, K. Li, and X. Meng, “Solvent-controlled switchable domino reactions of MBH carbonate: synthesis of benzothiophene fused α-pyran, 2,3-dihydrooxepine, and oxatricyclodecene derivatives,” Organic Letters, vol. 19, no. 22, pp. 6084–6087, 2017.

K. Li, A. Yu, and X. Meng, “Synthesis of dibenzothiophene and 1,4-dihydrodibenzothiophene derivatives via allylic phosphonium salt initiated domino reactions,” Organic Letters, vol. 20, no. 4, pp. 1106–1109, 2018.

S. Ma, A. Yu, L. Zhang, and X. Meng, “Phosphine-catalyzed domino reaction of thioaurones and allenoate: synthesis of benzothiophene-fused dioxabicyclo[3.3.1]nonane derivatives,” Journal of Organic Chemistry, vol. 83, no. 10, pp. 5410–5419, 2018.

S. Ma, A. Yu, and X. Meng, “Phosphine-catalyzed [4 + 2] annulation of γ-benzyl allenoates: facile synthesis of benzothieno[3,2-b]pyran derivatives,” Organic and Biomolecular Chemistry, vol. 16, no. 16, pp. 2885–2892, 2018.

CCDC 1882373 (3a) and 1888259 (4) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures/.