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Article

K2CO3-Mediated Synthesis of Functionalised 4-Substituted-2-amino-3-cyano-4H-chromenes via Michael-Cyclization Reactions

by
Yanyang He
1,†,
Rong Hu
1,†,
Rongsheng Tong
2,
Fengqiong Li
1,
Jianyou Shi
2,* and
Mei Zhang
1,*
1
Key Laboratory of Standardization of Chinese Herbal Medicines of Ministry of Education, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
2
Pharmaceutical Department of Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu 610072, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2014, 19(12), 19253-19268; https://doi.org/10.3390/molecules191219253
Submission received: 14 September 2014 / Revised: 23 October 2014 / Accepted: 5 November 2014 / Published: 25 November 2014
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
An efficient approach for the synthesis of functionalized 4-substituted-2-amino-3-cyano-4H-chromenes moderate to high yields (up to 98%) has been achieved via a tandem K2CO3 catalyzed conjugate addition-cyclization reaction of malononitrile and a range of Knoevenagel adducts previously formed from oxindole, pyrazolone, nitromethane, N,N-dimethylbarbituric acid or indanedione. This methodology differs from the previous classical methods in its simplicity and ready availability of the catalyst.

1. Introduction

In recent years, the chromene ring moiety has emerged as a privileged scaffold for drug design and discovery because it exists in a myriad of biological natural products [1], pharmaceutical agents and drug candidates [2]. Chromene derivatives have attracted increasing attention from synthetic chemists due to their diverse biological activities, including antitumor [3], antibacterial [4], antiviral [5], antioxidative [6], antidepressant [7], antihypertensive [8], antidiabetic [9], fungicidal [10], and insecticidal properties [11]. In particular, among the various chromene derivatives, 2-amino-4H-chroemnes have been reported to exhibit highly useful proapoptotic properties for the treatment of a wide range of cancer ailments [12,13]. In cancer chemotherapy, 2-amino-4H-chromene 1 (Figure 1) was marked for drug development due to its high inhibition of tumor-associated Bcl-2 proteins [14]. The further modified 4H-chromene structure 2 (Figure 1) was able to induce apoptosis (programmed cell death) in several cancer cell lines [15]. 4-Aryl-4H-chromene 3 was found to have potential ability in the enhancement of cognitive functions, thus it is used in the treatment of neurodegenerative diseases [16]. For diversity oriented synthesis, the structure of these bioactive molecules could provide opportunities for drug design in three important regions (the aromatic ring of the benzopyran, substitution at the C2-amine, and the substituted group at the C4 position).
Molecules 19 19253 g001 550
Figure 1. Selected examples of pharmacologically active compounds based on 4H-chromene scaffolds.
Figure 1. Selected examples of pharmacologically active compounds based on 4H-chromene scaffolds.
Molecules 19 19253 g001
As a result, considerable efforts have been made over the past decades for the synthesis of 2-amino-4H-chromenes [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47], which is accomplished using various catalysts including diethylamine [26], ethylenediamine diacetate [27], I2 [28], PEG [29], β-cyclodextrin [30], InCl3 [31,42,43], guanidine [32], ammonium acetate [46], Al2O3 [47], Zr(KPO4)2 [44], molecular sieves [45], aminosilane- modified Fe3O4 nanoparticles [33] and silica-bonded 2-hydroxyethylammonium acetate (HEAA) [34]. In addition, some enantioselective synthesis methodologies for 2-amino-4H-chromenes were also documented in the literature [22,23,35,36,37,38,39]. However, these methods show varying degrees of success as well as limitations, such as requiring complex and expensive catalytic systems, prolonged reaction times and complicated operations. Therefore, it is still deemed worthwhile and important to explore the direct use of an inexpensive and readily available organic species as catalyst for the above synthesis. The most straightforward synthesis of this heterocyclic nucleus involves the MCR of salicylaldehyde, malononitrile and nucleophiles, which can be catalyzed by various Lewis acids [22,23,31,42,43,44,47] (Scheme 1, previous work). It is worth mentioning that iminochromene was first formed, and then reacted with diverse C-, N-, S-, P-nucleophiles to give a wide range of substituted and fused chromenes. As part of our efforts toward the efficient synthesis of 2-amino-3-nitrile-4H-chromenes, we decided to seek a new class of readily available starting materials. A designed Michael addition triggered cascade reaction of malononitrile with Knoevenagel adducts generated from salicylaldehyde and nucleophiles was tested (Scheme 1, this work).
Molecules 19 19253 g002 550
Scheme 1. Strategies for the synthesis of substituted 2-amino-3-nitrile-4H-chromenes.
Scheme 1. Strategies for the synthesis of substituted 2-amino-3-nitrile-4H-chromenes.
Molecules 19 19253 g002
Therefore, in continuation of our interest in synthetic strategies for the preparation of heterocyclic compounds, a new K2CO3-catalyzed methodology for the synthesis of diverse 4-substituted-2-amino-3-cyano-4H-chromenes bearing various substituent groups at the C4 position was developed. These substituents are the most intensively studied structural motifs, and crucial building blocks for the synthesis of biologically active compounds and natural products [23] as key synthons in planning the synthesis of therapeutic agents and exhibiting diverse pharmaceutical activities.

2. Results and Discussion

Initially, the reaction of 3-(2-hydroxybenzylidene)-indolin-2-one (4a) and malononitrile (5) in THF was tested with different bases under mild conditions. Most organic bases such as DBU, piperidine, DIPEA and Et3N showed no activity within 2 h in this reaction (Scheme 1 and Table 1, entries 1–4). With the prolonged time, only a small amount of product was formed. Other organic bases such as DMAP and DABCO could promote the reaction and afforded the product 6a in low yield (31% and 13%, respectively, entries 5, 6). However, when the catalyst was replaced with an inorganic base, the reaction proceeded efficiently and was complete in less than 2 h at ambient temperature (Table 1, entries 7,8). Encouraged by the above results, more efforts were made to optimize other reaction parameters including solvents and reaction temperatures. Thus, the reaction was studied in different solvents that included THF, CH3OH, C2H5OH, CHCl3, CH2Cl2, H2O, toluene, dioxane, CH3CN and DMF (Table 1, entries 8–16). It was found that THF gave comparable yields (Table 1, entry 8), but other polar solvents, such as DMF, DMSO and water could not promote the reaction (Table 1, entries 11,13,14). The temperature also influenced the rate of the reaction. Increasing the reaction temperature resulted in a high reactivity (Table 1, entries 18–21), and conducting the reaction at 60 °C provided the best results. Notably, the two diastereoisomers of 6a could be easily isolated by silica gel chromatography and the diastereomer ratio was 1:1. Based on the comprehensive consideration of reaction temperature and yield, the optimal reaction conditions were established as shown in Table 1, entry 19. The ratio of two diastereomers remained the same in all the cases.
Table
Table 1. Optimization for the synthesis of 2-amino-4-(2-oxoindolin-3-yl)-4H-chromene 6a a.
Molecules 19 19253 i001
Table 1. Optimization for the synthesis of 2-amino-4-(2-oxoindolin-3-yl)-4H-chromene 6a a.
Molecules 19 19253 i001
EntrySolventBaseTemp.TimeYield of 6a b,c
1THFDBUr.t.2 h0
2THFPiperidiner.t.2 h0
3THFDIPEAr.t.2 h0
4THFEt3Nr.t.2 h0
5THFDMAPr.t.2 h31%
6THFDABCOr.t.2 h13%
7THFNa2CO3r.t.2 h61%
8THFK2CO3r.t.2 h95%
9CH3OHK2CO3r.t.2 h45%
10C2H5OHK2CO3r.t.2 h44%
11CH3ClK2CO3r.t.2 h34%
12CH2Cl2K2CO3r.t.2 h35%
13H2OK2CO3r.t.2 h0
14TolueneK2CO3r.t.2 h40%
15DioxaneK2CO3r.t.2 h0
16DMFK2CO3r.t.2 h0
17CH3CNK2CO3r.t.2 h66%
18THFK2CO340 °C50 min95%
19THFK2CO360 °C10 min98%
20CH3CNK2CO340 °C35 min91%
21CH3CNK2CO360 °C7 min98%
a Reaction conditions: 4a (0.1 mmol), 5 (0.1 mmol), Base (0.1 mmol) in solvent (0.5 mL). b Isolated yield after silica gel chromatography. c dr = 1:1 calculated from the isolated isomers.
After having established the optimal conditions for the synthesis of 2-amino-4-(2-oxoindolin-3-yl)-4H-chromene, the scope of reaction were explored with various Knoevenagel adducts derived from oxindole (Table 2). For the substrates bearing electron-donating (-Me) and electron-withdrawing groups (-Cl, -F) on the indole ring, the reactions proceeded smoothly to give the corresponding substituted 4H-chromenes 6 in 83%–98% yields. However, the Knoevenagel adducts with o-, m-substituents gave lower activity than those with p-substituents. In addition, the 3-F group (Table 2, entry 6) substrate gave a complex reaction mixture at 60 °C. Lowering the reaction temperature to room temperature, 6f was obtained in 85% yield by prolonging the reaction time. The diastereoselectivity of almost all of these reactions (except entry 13) was 1:1 and the two diastereoisomers could be isolated by silica gel chromatography. Thus, equivalent diastereoisomers were easily obtained in one step. This transformation was also suitable for ethyl cyanoacetate, furnishing compound 6l in 67% yields with higher diastereoselectivity (10:1).
Table
Table 2. Synthesis of new 2-amino-4-(2-oxoindolin-3-yl)-4H-chromene 6a–m a.
Molecules 19 19253 i002
Table 2. Synthesis of new 2-amino-4-(2-oxoindolin-3-yl)-4H-chromene 6a–m a.
Molecules 19 19253 i002
EntryR1R2R3R4Product 6TimeYield b,c
1HHHCN Molecules 19 19253 i00310 min98%
2H5-CH3HCN Molecules 19 19253 i0048 min 90%
3H5-ClHCN Molecules 19 19253 i0058 min95%
46-ClHHCN Molecules 19 19253 i0066 min93%
5H5-BrHCN Molecules 19 19253 i0076 min91%
6 dH3-FHCN Molecules 19 19253 i00815 h85%
7H4-FHCN Molecules 19 19253 i0092 h83%
8H5-FHCN Molecules 19 19253 i01010 min91%
95-FHHCN Molecules 19 19253 i0119 min89%
10HH-phCN Molecules 19 19253 i0125 min90%
11HH-CH3CN Molecules 19 19253 i01310 min87%
12 eHHH-COOEt Molecules 19 19253 i0143h67%
13 f Molecules 19 19253 i015 Molecules 19 19253 i01670 min70%
a All reactions were performed using 4 (0.1 mmol), 5 (0.1 mmol) in THF (0.5 mL). The products were characterized by 1H-NMR, 13C-NMR and MS. b Isolated yield after silica chromatography. c Diastereoisomer ratios (syn/anti = 1:1) calculated from the isolated isomers. d This reaction was performed in room temperature. e dr = 10:1. f Single isomer was obtained.
The structures of compounds 6a–m were confirmed by 1H-NMR, 13C-NMR and MS applied to all the diastereoisomers. In the 1H-NMR spectrum of compound 6a, the two key adjacent hydrogens were observed as two doublets at δ 3.67 ppm and 4.32 ppm. In the 13C-NMR spectrum, the characteristic meso methylene carbon resonated at δ 34.3 ppm (C-1) and 49.7 ppm (C-2), providing further evidence for the formation of the product. The NMR spectra of the other compounds 6b–m were consistent with previous reports.
To explore the scope and limitations of this reaction, we further extended the substrates to a variety of other substituents and heterocycles for the preparation of structurally diverse and functionalized 4-substituted-4H-chromenes. When Knoevenagel adducts derived from pyrazolone, nitromethane, N,N-dimethylbarbituric acid or indanedione were employed, we were pleased to find that the reactions proceeded smoothly in THF (0.5 mL) at 60 °C in 10 min to provide products 6n–q in good yield (75%–90%) (Table 3).
Table
Table 3. Synthesis of more substituted 4H-chromenes 6n–q a,b.
Molecules 19 19253 i017
Table 3. Synthesis of more substituted 4H-chromenes 6n–q a,b.
Molecules 19 19253 i017
Molecules 19 19253 i018
a All reactions were performed using 4 (0.1 mmol), 5 (0.1 mmol) in THF (0.5 mL) at 60 °C in 5, 12, 40, 10 min, respectively. The products were characterized by 1H-NMR, 13C-NMR and MS. b Isolated yield after silica gel chromatography.

3. Experimental Section

3.1. General Information

All chemicals were obtained from commercial sources and used without further purification. Column chromatography was carried out on silica gel (300–400 mesh, Qingdao Marine Chemical Ltd., Qingdao, China). Thin layer chromatography (TLC) was performed on TLC silica gel 60 F254 plates.1H-NMR spectra were recorded on a Bruker AVII-400 or AVII-600 MHz NMR spectrometer. The chemical shifts were recorded in ppm relative to tetramethylsilane and with the solvent resonance as the internal standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartlet, m = multiplet), coupling constants (Hz), integration. 13C-NMR data were collected at 100 MHz with complete proton decoupling. Chemical shifts were reported in ppm from the tetramethylsilane with the solvent resonance as internal standard. MS spectra were obtained on a Waters Quattro Premier XETM triple quadrupole mass spectrometer and methanol was used to dissolve the sample. Melting points were recorded on a SGW X-4 melting point instrument (Shanghai Precision & Scientific Instrument Co., Ltd, Shanghai, China).

3.2. Experimental Procedures

A mixture of 1,3-dihydro-3-[(2-hydroxyphenyl)methylene]-2H-indol-2-one (4a, 0.1 mmol), malononitrile (5a, 0.1 mmol) and K2CO3 (0.1 mmol) was stirred in THF (0.5 mL) for 10 min at 60 °C. After completion of the reaction (TLC), the solvent was removed under vacuum. The crude product was subjected to column chromatography on silica gel using petroleum ether/ethyl acetate = 1:1 as the eluent to give 6a. Compounds 6b–q were synthesized by a similar procedure as described for compound 6a. For the separation of these compounds, the silica gel column chromatography eluent consisted of appropriate mixtures of petroleum ether and ethyl acetate.
2-Amino-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6a). Isomer 6aa: White solid; m.p. 192–194 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.67 (d, J = 2.8 Hz, 1H), 4.32 (d, J = 2.8 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 6.71 (s, 2H), 6.76–6.81 (m, 2H), 7.02 (d, J = 8.0 Hz, 1H), 7.11–7.16 (m, 2H), 7.23–7.25 (m, 1H), 7.30–7.34 (m, 1H), 10.41 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 36.6, 50.5, 53.1, 109.2, 115.8, 120.0, 120.9, 121.5, 123.5, 124.6, 126.8, 128.0, 128.2, 128.6, 143.5, 149.7, 162.1, 176.0; MS: m/z = 326 [M+Na]+. Isomer 6ab: White solid; m.p. 191–193 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.63 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 2.8 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 8.0 Hz, 1H), 6.98–7.07 (m, 2H), 7.09–7.19 (m, 5H), 10.43 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 37.2, 52.4, 52.7, 109.1, 115.6, 119.7, 120.2, 121.1, 123.6, 124.2, 126.6, 127.6, 128.0, 128.4, 142.9, 149.3, 161.9, 176.7; MS: m/z = 326 [M+Na]+.
2-Amino-6-methyl-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6b). Isomer 6ba: White solid; m.p. 209–211 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 2.16 (s, 3H), 3.62 (d, J = 3.2 Hz, 1H), 4.19 (d, J = 3.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.82–6.86 (m, 1H), 6.90–6.93 (m, 1H), 6.96 (s, 1H), 7.03–7.07 (m, 3H), 7.17 (d, J = 7.6 Hz, 1H), 10.45 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 20.3, 37.2, 52.2, 52.7, 109.1, 115.3, 119.4 120.3, 121.1, 123.7, 126.7, 127.8, 128.0, 128.9, 133.0, 143.0, 147.3, 162.1, 176.7; MS: m/z = 340 [M+Na]+. Isomer 6bb: White solid; m.p. 136–139 °C; 1H-NMR (400 MHz, TMS, CDCl3): δ 2.29 (s, 3H), 3.68 (d, J = 3.2 Hz, 1H), 4.43 (d, J = 3.2 Hz, 1H), 4.65 (s, 2H), 6.46 (d, J = 7.2 Hz, 1H), 6.83–6.89 (m, 3H), 6.98 (s, 1H), 7.06–7.08 (m, 1H), 7.16–7.20 (m, 1H), 8.79 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ 20.8, 37.4, 53.5, 53.7, 110.1, 116.1, 120.1, 120.6, 122.0, 124.2, 126.4, 128.3, 128.5, 129.4, 135.0, 142.6, 147.9, 162.1, 177.4; MS: m/z = 340 [M+Na]+.
2-Amino-6-chloro-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6c). Isomer 6ca: White solid; m.p. 183–184 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.67 (d, J = 3.2 Hz, 1H), 4.26 (d, J = 3.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.83–6.89 (m, 2H), 7.07–7.23 (m, 6H), 10.53 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 37.5, 52.1, 53.2, 109.7, 118.0, 120.3, 121.8, 122.6, 124.4, 126.9, 127.8, 128.1, 128.7, 128.8, 143.4, 148.8, 162.3, 177.1; MS: m/z = 360 [M+Na]+. Isomer 6cb: White solid; m.p. 170–172 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.72 (d, J = 3.2 Hz, 1H), 4.33 (d, J = 3.2 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.76–6.85 (m, 4H), 7.05 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.24–7.25 (m, 1H), 7.34–7.37 (m, 1H), 10.40 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 37.0, 50.6, 53.2, 109.7, 118.2, 120.4, 121.5, 123.9, 124.1, 127.1, 128.4, 128.6, 128.7, 129.0, 144.0, 149.0, 162.4, 176.4; MS: m/z = 360 [M+Na]+.
2-Amino-4-(6-chloro-2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6d). Isomer 6da: White solid; m.p. 184–186 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.67 (d, J = 3.2 Hz, 1H), 4.26 (d, J = 3.2 Hz, 1H), 6.63–6.64 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.93 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.01–7.20 (m, 6H), 10.57 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 37.2, 51.9, 52.5, 109.1, 115.7, 119.7, 120.1, 120.8, 124.3, 125.1, 125.8, 127.6, 128.6, 132.3, 144.5, 149.3, 162.0, 176.6; MS: m/z = 360 [M+Na]+. Isomer 6db: White solid; m.p. 179–182 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.69 (d, J = 2.8 Hz, 1H), 4.32 (d, J = 2.8 Hz, 1H), 6.40 (d, J = 8.0 Hz, 1H), 6.73 (s, 2H), 6.78 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.27–7.35 (m, 2H), 10.56 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 36.6, 49.9, 52.8, 109.2, 115.9, 120.0, 120.6, 121.2, 124.8, 124.9, 125.8, 128.3, 128.8, 132.4, 145.1, 149.6, 162.1, 176.1; MS: m/z = 360 [M+Na]+.
2-Amino-6-bromo-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6e). Isomer 6ea: White solid; m.p. 118–120 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.66 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 2.8 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 8.0 Hz, 1H), 6.87 (t, J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.14 (s, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 10.53 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 36.9, 51.7, 52.7, 109.2, 115.6, 117.9, 119.8, 121.3, 122.6, 123.9, 126.4, 128.2, 130.2, 131.2, 142.9, 148.8, 161.7, 176.5; MS: m/z = 382 [M+H]+. Isomer 6eb: White solid; m.p. 172–175 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.71 (d, J = 3.2 Hz, 1H), 4.33 (d, J = 3.2 Hz, 1H), 6.57 (d, J =7.6 Hz, 1H), 6.76–6.85 (m, 4H), 6.98 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.34–7.35 (m, 1H), 7.47 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 10.39 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 36.4, 50.2, 52.7, 109.2, 116.0, 118.0, 119.9, 121.1, 123.6, 123.8, 126.6, 128.2, 130.8, 131.4, 143.5, 148.9, 161.8, 175.9; MS: m/z = 380 [M−H]−.
2-Amino-8-fluoro-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6f). Isomer 6fa: White solid; m.p. 197–199 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.66 (d, J = 3.2 Hz, 1H), 4.29 (d, J = 3.2 Hz, 1H), 4.63 (d, J = 8.0 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 6.97–7.11 (m, 4H), 7.19–7.24 (m, 3H), 10.43 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 37.0, 52.3, 52.7, 109.1, 115.1(d, J = 7 Hz), 119.7, 121.2, 122.7, 122.9 (d, J = 3 Hz), 123.7, 124.2 (d, J = 7 Hz), 126.4, 128.2, 137.5 (d, J = 11 Hz), 143.0, 149.1(d, J = 245 Hz), 161.3, 176.5; MS: m/z = 344 [M+Na]+. Isomer 6fb: White solid; m.p. 133–135 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.68 (d, J = 2.8 Hz, 1H), 4.36 (d, J = 2.8 Hz, 1H), 4.56 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.82–6.89 (m, 3H), 6.98 (d, J = 8.0 Hz, 1H), 7.09–7.18 (m, 2H), 7.24–7.29 (m, 1H), 10.39 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 36.5, 50.6, 52.8, 109.3, 115.2(d, J = 17Hz), 119.8, 121.1, 123.4 (d, J = 3 Hz), 123.5, 124.0, 124.5(d, J = 7 Hz), 126.6, 128.2, 137.8 (d, J = 11Hz), 143.5, 149.3 (d, J = 245Hz), 161.4, 175.9; MS: m/z = 344 [M+Na]+.
2-Amino-7-fluoro-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6g). Isomer 6ga: White solid; m.p. 167–169 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.62 (d, J = 2.8 Hz, 1H), 4.23 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.68–6.71 (m, 1H), 6.84–6.93 (m, 2H), 7.07 (t, J = 8.0 Hz, 1H), 7.16–7.20 (m, 4H), 10.44 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 36.8, 52.4, 52.7, 103.1 (d, J = 25 Hz), 109.1, 111.3 (d, J = 22 Hz), 116.1, 119.9, 121.2, 123.7, 126.5, 128.1, 129.1(d, J = 10 Hz), 142.9, 150.0 (d, J = 12 Hz), 161.1 (d, J = 243 Hz), 161.5, 176.6; MS: m/z = 344 [M+Na]+. Isomer 6gb: White solid; m.p. 165–169 °C; 1H-NMR (400 MHz, TMS, DMSO): δ3.66 (d, J = 2.8 Hz, 1H), 4.31 (d, J = 2.8 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.68–6.71 (m, 1H), 6.75–6.86 (m, 3H), 6.89–6.94 (m, 1H), 6.96–7.02 (m, 1H), 7.04–7.10 (m, 1H), 7.13–7.26 (m, 1H), 10.38 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 36.1, 50.5, 52.9, 103.3 (d, J = 25 Hz), 109.2, 111.7 (d, J = 22 Hz), 119.9, 121.1, 123.6, 126.7, 128.1, 129.4 (d, J = 10 Hz), 129.8 (d, J = 10 Hz), 143.5, 150.2 (d, J = 12 Hz), 161.4 (d, J = 245 Hz), 161.7, 176.0; MS: m/z = 344 [M+Na]+.
2-Amino-6-fluoro-4-(2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6h). Isomer 6ha: White solid; m.p. 212–217 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.66 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 2.8 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.82–6.88 (m, 2H), 6.93–7.01 (m, 2H), 7.05–7.11 (m, 3H), 7.18–7.20 (m, 1H), 10.49 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 37.3, 51.5, 52.6, 109.1, 113.7 (d, J = 24 Hz), 115.2 (d, J = 24 Hz), 117.3 (d, J = 8 Hz), 120.0, 121.3, 121.7 (d, J = 8 Hz), 123.8, 126.4, 128.1, 142.9, 145.7, 157.8 (d, J = 238 Hz), 161.9, 176.6; MS: m/z = 344 [M+Na]+. Isomer 6hb: White solid; m.p. 202–203 °C; 1H-NMR (400 MHz, TMS, DMSO): δ3.72 (d, J = 2.8 Hz, 1H), 4.33 (d, J = 2.8 Hz, 1H), 6.49 (d, J = 7.6 Hz, 1H), 6.72 (s, 2H), 6.76–6.83 (m, 2H), 7.04–7.10 (m, 2H), 7.14–7.18 (m, 2H), 10.40 (s, 1H); 13C-NMR (100 MHz, DMSO): δ36.7, 49.7, 52.7, 109.3, 114.4 (d, J = 24 Hz), 115.5 (d, J = 24 Hz), 117.4, 117.5, 119.9, 121.0, 123.2, 123.3, 123.5, 126.6, 128.1, 144.8 (d, J = 249 Hz), 162.1, 175.9; MS: m/z = 344 [M+Na]+.
2-Amino-4-(5-fluoro-2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6i). Isomer 6ia: White solid; m.p. 183–185 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.68 (d, J = 2.8 Hz, 1H), 4.26 (d, J = 2.8 Hz, 1H), 6.58–6.61 (m, 1H), 6.82–6.84 (m, 1H), 6.87–6.93 (m, 1H), 6.99–7.05 (m, 2H), 7.12–7.19 (m, 4H), 10.43 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 37.1, 50.7.6, 54.0, 110.2, 110.3, 111.7.0 (d, J = 25 Hz), 114.8 (d, J = 23 Hz), 116.1, 120.5, 121.6, 124.8, 128.2, 128.8, 140.3, 150.2, 157.9 (d, J = 234 Hz), 162.7, 176.4; MS: m/z = 344 [M+Na]+. Isomer 6ib: White solid; m.p. 130–134 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.71 (d, J = 2.8 Hz, 1H), 4.34 (d, J = 2.8 Hz, 1H), 6.73–6.77 (m, 3H), 6.96–7.05 (m, 2H), 7.12–7.17 (m, 2H), 7.24–7.25 (m, 1H), 7.32–7.36 (m, 1H), 10.43 (s, 1H); 13C-NMR (100 MHz, DMSO): δ37.1, 50.7, 54.0, 110.2, 110.3, 111.7 (d, J = 24 Hz), 114.8 (d, J = 24 Hz), 116.3, 120.5, 121.6, 125.3, 128.8, 129.3, 140.3, 150.2, 157.8 (d, J = 235 Hz), 162.7, 176.4; MS: m/z = 344 [M+Na]+.
2-Amino-4-(2-oxo-1-phenylindolin-3-yl)-4H-chromene-3-carbonitrile (6j). Isomer 6ja: White solid; m.p. 186–187 °C; 1H-NMR (400 MHz, TMS, CDCl3): δ 3.95 (d, J = 3.2 Hz, 1H), 4.55 (d, J = 3.2 Hz, 1H), 4.92 (s, 2H), 6.50 (d, J = 8.0 Hz, 1H), 6.74 (t, J = 8.0 Hz, 1H), 6.97–7.00 (m, 2H), 7.05–7.12 (m, 2H), 7.20–7.24 (m, 3H), 7.36 (d, J = 8.0Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.47–7.51 (m, 2H); 13C-NMR (100 MHz, DMSO): δ 29.7, 38.2, 52.6, 109.1, 116.0, 118.8, 119.4, 122.9, 124.4, 124.6, 125.5, 126.5, 128.1, 128.2, 128.3, 128.7, 129.6, 134.2, 144.6, 149.5, 161.6, 174.8; MS: m/z = 402 [M+Na]+. Isomer 6jb: White solid; m.p. 192–194 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.97 (d, J = 2.8 Hz, 1H), 4.45 (d, J = 2.8 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.79 (s, 2H), 6.92 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.35–7.40 (m, 3H), 7.45 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H) ; MS: m/z = 402 [M+Na]+.
2-Amino-4-(1-methyl-2-oxoindolin-3-yl)-4H-chromene-3-carbonitrile (6k). Isomer 6ka: White solid; m.p. 208–211 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.02 (s, 3H), 3.68 (d, J = 3.2 Hz, 1H), 4.26 (d, J = 3.2 Hz, 1H), 6.73–6.76 (m, 2H), 6.90–7.02 (m, 3H), 7.06–7.16 (m, 4H), 7.21 (d, J = 7.2Hz, 1H); 13C-NMR (100 MHz, DMSO): δ 25.8, 37.7, 52.1, 52.3, 108.0, 115.6, 119.2, 120.2, 121.8, 123.4, 124.0, 125.7, 127.2, 128.1, 128.5, 144.4, 149.2, 161.9, 174.7; MS: m/z = 340 [M+Na]+. Isomer 6kb: White solid; m.p. 202–205 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.07 (s, 3H), 3.75 (d, J = 2.8 Hz, 1H), 4.34 (d, J = 2.8 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 6.64 (s, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 7.16–7.22 (m, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.32–7.39 (m, 2H); 13C-NMR (100 MHz, DMSO): δ 26.0, 37.0, 49.5, 52.6, 108.2, 115.8, 119.7, 121.2, 121.6, 123.1, 124.8, 125.9, 128.2, 128.4, 128.7, 145.0, 149.5, 161.9, 174.3; MS: m/z = 340 [M+Na]+.
ethyl 2-Amino-4-(2-oxoindolin-3-yl)-4H-chromene-3-carboxylate (6l). White solid; m.p. 93–96 °C; 1H-NMR (400 MHz, TMS, DMSO): δ1.38 (t, J = 7.2 Hz, 3H), 3.87 (d, J = 3.2 Hz, 1H), 4.30–4.36 (m, 2H), 4.77 (d, J = 3.2 Hz, 1H), 6.60–6.66 (m, 2H), 6.84–6.90 (m, 2H), 6.97–7.06 (m, 2H), 7.23–7.28 (m, 2H), 8.32 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 14.7, 36.7, 53.2, 59.8, 75.5, 109.1, 115.3, 121.4 122.1, 124.1, 124.6, 127.3, 127.8, 127.9, 128.4, 141.6, 149.9, 162.1, 169.1, 178.7; MS: m/z = 373 [M+Na]+.
2-Amino-4-(2-oxoindolin-3-yl)-4H-benzo[g]chromene-3-carbonitrile (6m). White solid; m.p. 201–205 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.69 (d, J = 2.8 Hz, 1H), 4.90 (d, J = 2.8 Hz, 1H), 6.24 (d, J = 7.2 Hz, 1H), 6.72–6.76 (m, 3H), 6.82 (d, J = 7.6 Hz, 1H), 7.11–7.15 (m, 1H), 7.30 (d, J = 9.2 Hz, 1H ), 7.55–7.59 (m, 1H), 7.71–7.75 (m, 1H), 8.00–8.05 (m, 2H), 8.13 (d, J = 8.4 Hz, 1H), 10.62 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 34.3, 49.7, 51.5, 109.4, 114.6, 116.6, 119.9, 121.0, 122.0, 123.4, 125.3, 126.5, 127.9, 128.0, 129.1, 129.2, 129.8, 130.9, 143.8, 147.6, 162.1, 176.5; MS: m/z = 376 [M+Na]+.
2-Amino-4-(nitromethyl)-4H-chromene-3-carbonitrile (6n). White solid; m.p. 144–146 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 4.32 (t, J = 5.2 Hz, 1H), 4.67 (dd, J = 12.0 Hz, J =5.2 Hz, 1H), 4.80 (dd, J = 12.0 Hz, J =5.2 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.17–7.21 (m, 3H), 7.31–7.36 (m, 2H); 13C-NMR (100 MHz, DMSO): δ 34.6, 49.9, 80.7, 116.1, 119.4, 119.7, 124.7, 128.3, 129.1, 149.4, 162.1; MS: m/z = 254 [M+Na]+.
2-Amino-4-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-4H-chromene-3-carbonitrile (6o). White solid; m.p. 150–152 °C; 1H-NMR (600 MHz, TMS, DMSO): δ 1.83 (s, 3H), 4.93 (s, 1H), 6.65 (s, 2H), 6.94–7.05 (m, 2H), 7.15–7.20 (m, 3H), 7.26–7.29 (m, 4H), 7.88–7.90 (m, 2H); MS: m/z = 383 [M+K]+.
2-Amino-4-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4H-chromene-3-carbonitrile (6p). White solid; m.p. 85–88 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.61 (d, J = 2.8 Hz, 1H), 4.35 (d, J = 2.8 Hz, 1H), 6.94–7.11 (m, 3H), 7.19–7.23 (m, 1H), 7.87–7.92 (m, 4H); MS: m/z = 315 [M−H]−.
2-Amino-4-(1,3-dimethyl-2,4,6-trioxohexahydropyrimidin-5-yl)-4H-chromene-3-carbonitrile (6q). White solid; m.p. 195–198 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.01 (s, 3H), 3.07 (s, 3H), 3.67 (d, J = 2.8 Hz, 1H), 4.37 (d, J = 2.8 Hz, 1H), 6.98–7.00 (m, 1H), 7.16–7.20 (m, 2H), 7.30–7.32 (m, 1H); MS: m/z = 325 [M−H]−.

4. Conclusions

In conclusion, we have demonstrated an efficient approach for the synthesis of functionalised 4-substituted-2-amino-3-cyano-4H-chromenes via a tandem conjugate addition-cyclization reaction of malononitrile and a range of Knoevenagel adducts using K2CO3 as catalyst. A range of 4-substituted-2-amino-3-cyano-4H-chromenes were thus obtained in moderate to high yields (up to 98%). This synthetic method offers several advantages, including milder reaction conditions, an economical catalyst system, shorter time for completion and simple process, all which make it an efficient route for the synthesis of 2-amino-4H-chromenes. Moreover, for 4-indolylchromenes, the two isomers formed could be isolated one step silica gel chromatography. Further study on the antibacterial and antitumor activities of these compounds is underway.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/19/7/10218/s1.

Acknowledgments

We appreciate the financial support of National Natural Science Foundation of China (No. 81302643), China Postdoctoral Science Foundation (No. 2014M552374), and Sichuan Provincial Health Department Research Project (No. 120077). We are also grateful to Xiaoyan Wang (Sichuan University Analytical & Testing Center) for the NMR analysis.

Author Contributions

Jianyou Shi and Mei Zhang designed research; Yanyang He, Rong Hu, Rongsheng Tong and Fengqiong Li performed research. All authors read and approved the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.

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MDPI and ACS Style

He, Y.; Hu, R.; Tong, R.; Li, F.; Shi, J.; Zhang, M. K2CO3-Mediated Synthesis of Functionalised 4-Substituted-2-amino-3-cyano-4H-chromenes via Michael-Cyclization Reactions. Molecules 2014, 19, 19253-19268. https://doi.org/10.3390/molecules191219253

AMA Style

He Y, Hu R, Tong R, Li F, Shi J, Zhang M. K2CO3-Mediated Synthesis of Functionalised 4-Substituted-2-amino-3-cyano-4H-chromenes via Michael-Cyclization Reactions. Molecules. 2014; 19(12):19253-19268. https://doi.org/10.3390/molecules191219253

Chicago/Turabian Style

He, Yanyang, Rong Hu, Rongsheng Tong, Fengqiong Li, Jianyou Shi, and Mei Zhang. 2014. "K2CO3-Mediated Synthesis of Functionalised 4-Substituted-2-amino-3-cyano-4H-chromenes via Michael-Cyclization Reactions" Molecules 19, no. 12: 19253-19268. https://doi.org/10.3390/molecules191219253

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