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. 2019 Feb 7;4(2):2863–2873. doi: 10.1021/acsomega.8b03284

Three-Component Cascade Reaction of 1,1-Enediamines, N,N-Dimethylformamide Dimethyl Acetal, and 1,3-Dicarbonyl Compounds: Selective Synthesis of Diverse 2-Aminopyridine Derivatives

Quan-Xing Zi 1, Sheng-Jiao Yan 1,*, Chang-Long Yang 1, Kun Li 1, Jun Lin 1,*
PMCID: PMC6648487  PMID: 31459516

Abstract

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A novel approach has been developed for the synthesis of three kinds of highly functionalized 2-aminopyridine derivatives (APDs) through a three-component reaction of 1,1-enediamines (EDAMs) 1, N,N-dimethylformamide dimethyl acetal (DMF-DMA) 2, and 1,3-dicarbonyl compounds 3–5 via a base-promoted cascade reaction, producing the desired products in good to excellent yields. This method represents a route to obtain a novel class of APDs in a concise, rapid, and practical manner. This approach is particularly attractive because of the following features: low cost, mild temperature, atom economy, high yields, and potential biological activity of the product.

Introduction

The 2-aminopyridine derivatives (APDs) are one of the most important classes of N-containing heterocycles, which are also ubiquitous structural motifs in natural or synthetic biologically active molecules or drugs. This kind of compounds usually have broad spectrum biological activity, including anti-HIV,1 antitumor2−9 (Figure 1; Crizotinib2,3 and Asciminib4), anti-inflammatory,10 antifungal,11 antihistamine,12,13 antidepressant, antiarthritic, santidiabetic, antiglaucoma,14 and antiprion (Figure 1).15 These derivatives are widely used as inhibitors of a variety of proteins, such as activin A receptor type 1 (ACVR1),16 nitric oxide synthase 1 (NOS1),17,18 A2A adenosine receptor (ADORA2A) (Figure 1),19 and so forth.20 Consequently, various methods for the synthesis of 2-aminopyridines have been developed.21−27 The classic methods include the nucleophilic substitution reaction (SN) of 2-bromopyridines (Scheme 1a),21,22 ruthenium-catalyzed cyclization reaction (Scheme 1b),23 nucleophilic reagents reaction with in situ generated 1,4-oxazepines from N-propargylic β-enaminones followed by spontaneous N-deformylation to APDs (Scheme 1c),24,25 and ruthenium-mediated [2 + 2 + 2] cycloaddition of α,ω-diynes and cyanamides (Scheme 1d).26 Although these methods have been very valuable in the synthesis of APDs, they generally have some shortcomings, including the complexity of the structure of the substrates for the synthesis of APDs requires multistep and hazardous processes for its construction, the approach often requires harsh conditions such as the use of a metal-catalyst, and the yield and atom economy do not meet the demands of medical and biological research.

Figure 1.

Figure 1

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Bioactive 2-aminopyridines, indenopyridines, and the target compounds 6–8.

Scheme 1. Methods for the Synthesis of APDs.

Scheme 1

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In addition, indanone derivatives are considerably important because of their interesting biological activities.28−30 Among them, indenopyridine derivatives are an important class of pharmaceuticals and bioactive natural products as a result of their significant and wide-spectrum biological activities and are widely used as antitumor or antiproliferative drugs,28,29 antimalarial agents, and ADORA2A antagonist agents (Figure 1).19 Although there are some methods for the synthesis of these molecules,28−32 these methods require multistep synthesis and strict anhydrous conditions. Thus, there is a need for the development of concise and effective methods for preparing the target compound library.

The 1,1-enediamines (EDAMs) are a variety of building blocks that are usually used as bis-nucleophiles (α-carbon and N as nucleophilic sites) to react with bis-electrophiles and produce heterocyclic compounds, including pyridin-2-ones, pyrimidin-4-ones, imidazopyridinium derivatives, and morphan derivatives.33−40 As part of our ongoing research effort, we used EDAMs as a substrate to react with dimethylformamide dimethyl acetal (DMF-DMA) 2 and 1,3-dicarbonyl compounds 3 for the synthesis of 2-aminopyridines 6 (Scheme 1). Notably, the reaction for synthesis of the target compounds 6 is completely different from the reported reaction. In this study, the C(1) of EDAMs 1 serves to attack the electrophilic sites C(1) of 1,3-dicarbonyl compounds 3 maybe as a result of the high eletrophilicity of the C(1) of substrate 3 and the little steric effects of the R′ group of compound 3. In addition, on the basis of the splicing principle of the molecular structure of the drug, we combined the two active core structures (cyclohexanone/indanone and 2-aminopyridine) in the target compounds with the aim of producing a new class of pharmaceutical molecule which may possess potential biological activities. Accordingly, the cyclohexanone-fused APDs 7 and the indenopyridine derivatives 8 were easily prepared by this method. Here, the N(2) of EDAMs 1 serves to attack the electrophilic sites C(1) of 1,3-dicarbonyl compounds 4/5 maybe as a result of the low eletrophilicity of the C(1) of substrate 4/5 and the steric effects of the R′ group of compound 4/5 (Scheme 1). Therefore, we can successfully regioselectively synthesize three kinds of 2-aminopyridines based on the structural difference of the substrates 3–5 (Scheme 1). This approach provides the key information to design new substrates to react with EDAMs to synthesize various 2-aminopyridines, 2-aminoquinolones, 2-aminopyrroles, 2-aminoindoles, and so forth, via one-pot multicomponent reactions rather than multistep synthesis.

Results and Discussion

To find the optimal reaction conditions for the synthesis of our target molecule, the reaction of (Z)-N-(4-methylphenethyl)-2-nitroethene-1,1-diamine 1b, DMF-DMA 2 and ethyl 3-oxobutanoate (3a) was chosen as the model reaction. First, the three-component reaction was performed in different solvents, which included acetone, ethanol, acetonitrile, and 1,4-dioxane, at reflux conditions (Table 1, entries 1–4). The results showed that the reaction could not proceed at all. Then, Cs2CO3 was added to the mixture as a promoter in the above-mentioned solvents at the reflux temperature (Table 1, entries 5–8). The results revealed that the reaction promoted by Cs2CO3 still could not proceed in acetone, ethanol, or acetonitrile (Table 1, entries 5–7). Fortunately, however, when 1,4-dioxane was used as the solvent under the same conditions, the reaction produced the target compound with an excellent yield (88%) (Table 1, entry 8). The use of another inorganic base, namely, K2CO3, as promoter with acetonitrile or 1,4-dioxane as solvent and at reflux conditions, revealed that only when using 1,4-dioxane the reactions proceed smoothly and can produce the target compound in good yield (Table 1, entry 10). On the basis of these results, the stronger organic base potassium tert-butoxide (t-BuOK) was separately added to acetone, ethanol, acetonitrile or 1,4-dioxane at reflux conditions for 12 h (Table 1, entries 11–14). The results indicated that positive results can only be obtained with 1,4-dioxane (Table 1, entry 14). On the basis of the above findings, we concluded that 1,4-dioxane is the optimal solvent for this reaction. We also compared yields obtained with the three promoters K2CO3, Cs2CO3, and t-BuOK and found that the best promoter is Cs2CO3 (Table 1, entry 8 vs 10 &14). Next, the reaction times were evaluated (Table 1, entry 8 vs 15). We found that the best reaction time was about 5 h. Finally, we additionally examined the effects of the amount of promoter on the reaction yields. When the amount of catalyst Cs2CO3 was adjusted to 10% (0.01 mmol) of the amount of substrate 1b, the reaction produced the target compound 6a with a 90% yield (Table 1, entry 16 vs 15). Accordingly, we assumed that 0.05 equiv Cs2CO3 was sufficient for this reaction.

Table 1. Optimization of the Reaction Conditiona.

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entry solvent catalyst T (°C) t (h) yieldb (%)
1 acetone   reflux 12 n.r
2 EtOH   reflux 12 n.r
3 acetonitrile   reflux 12 n.r
4 1,4-dioxane   reflux 12 n.r
5 acetone Cs2CO3c reflux 12 n.r
6 EtOH Cs2CO3c reflux 12 n.r
7 acetonitrile Cs2CO3c reflux 12 n.r
8 1,4-dioxane Cs2CO3c reflux 12 88
9 acetonitrile K2CO3c reflux 12 n.r
10 1,4-dioxane K2CO3c reflux 12 85
11 acetone t-BuOkc reflux 12 n.r
12 EtOH t-BuOkc reflux 12 n.r
13 acetonitrile t-BuOkc reflux 12 n.r
14 1,4-dioxane t-BuOkc reflux 12 86
15 1,4-dioxane Cs2CO3c reflux 5 91
16 1,4-dioxane Cs2CO3d reflux 5 90
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a

Reaction conditions: EDAM 1b (1.0 mmol), DMF-DMA 2 (1.5 mmol), 3a (1.0 mmol) and solvent (8 mL).

b

Isolated yield based on 1b.

c

Catalyst (0.05 mmol).

d

Catalyst (0.1 mmol).

With the optimal conditions in hand, we explored the scope and limitations of the three-component cascade reaction with various EDAMs and a variety of 1,3-dicarbonyl compounds. The results revealed that in all cases the reaction proceeded smoothly in 1,4-dioxane at reflux conditions for about 5 h (Table 2, entries 1–16). The different substituent groups (R) of the EDAMs 1 usually had a slight effect on the yields, but the difference is very small, and we cannot ascertain the effect of any specific substituent. However, the substituent group of 1,3-dicarbonyl compounds 3 has an obvious effect on the yield of compounds 6. In general, the substrates 3a and 3b are usually more favorable to the yield of the target compounds than the substrates 3c–3e. Overall, the different substituted substrates 1 and 3 easily reacted with DMF-DMA 2 to produce compound 6 with good to excellent yields (74–92%).

Table 2. Synthesis of 2-Aminopyridines 6a.

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entry R R′ R″ 1 3 6 yieldb (%)
1 p-CH3C6H4CH2CH2 CH3 OCH2CH3 1b 3a 6a 91
2 C6H5CH2CH2 CH3 OCH2CH3 1c 3a 6b 91
3 m-FC6H4CH2CH2 CH3 OCH2CH3 1d 3a 6c 92
4 p-ClC6H4CH2 CH3 OCH2CH3 1f 3a 6d 91
5 p-FC6H4CH2 CH3 OCH2CH3 1g 3a 6e 91
6 p-CH3OC6H4CH2CH2 CH3 CH3 1a 3b 6f 89
7 p-CH3C6H4CH2CH2 CH3 CH3 1b 3b 6g 92
8 C6H5CH2CH2 CH3 CH3 1c 3b 6h 91
9 m-FC6H4CH2CH2 CH3 CH3 1d 3b 6i 92
10 o-FC6H4CH2CH2 CH3 CH3 1e 3b 6j 91
11 p-ClC6H4CH2 CH3 CH3 1f 3b 6k 90
12 p-CH3C6H4CH2CH2 CF3 CF3 1b 3c 6l 87
13 m-FC6H4CH2CH2 CF3 CF3 1e 3c 6m 85
14 p-ClC6H4CH2 CF3 Ph 1f 3d 6n 84
15 C6H5CH2CH2 Ph Ph 1c 3e 6o 76
16 m-FC6H4CH2CH2 Ph Ph 1e 3e 6p 74
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a

Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), 3 (1.0 mmol), and solvent (8 mL).

b

Isolated yield based on 1.

To further investigate the scope and limitations of the cascade reaction, we reacted cyclic 1,3-dicarbonyl compounds (cyclohexane-1,3-dione derivatives) with various EDAMs 1 and DMF-DMA 2, and we find that the optimal reaction time is about 10 h. Interestingly, the reaction produced another kind of 2-aminopyridines 7 (Table 3, entries 1–14). In this reaction, the C(1) of EDAMs 1 serves to attack the electrophilic sites C(1′) of the intermediate formed from substrate 4 and DMF-DMA 2 (Schemes 1 and 2). Thus, different substituted EDAMs were also used as a substrate and reacted with DMF-DMA and cyclohexane-1,3-dione derivatives 4a–4b, which all produced the target compounds 7 with excellent yields, except for compound 7h (Table 3, entries 1–14). The substituted groups on substrates 1 and 4 had almost no effect on the yield, which indicated that various substrates can produce ideal results.

Table 3. Synthesis of APDs 7a.

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entry R R′ 1 4 7 yieldb (%)
1 p-CH3OC6H4CH2CH2 CH3 1a 4a 7a 90
2 p-CH3C6H4CH2CH2 CH3 1b 4a 7b 92
3 C6H5CH2CH2 CH3 1c 4a 7c 92
4 m-FC6H4CH2CH2 CH3 1d 4a 7d 90
5 o-FC6H4CH2CH2 CH3 1e 4a 7e 90
6 p-ClC6H4CH2 CH3 1f 4a 7f 90
7 p-FC6H4CH2 CH3 1g 4a 7g 91
8 C6H5 CH3 1h 4a 7h 76
9 p-CH3OC6H4CH2CH2 H 1a 4b 7i 90
10 p-CH3C6H4CH2CH2 H 1b 4b 7j 92
11 C6H5CH2CH2 H 1c 4b 7k 91
12 m-FC6H4CH2CH2 H 1d 4b 7l 90
13 o-FC6H4CH2CH2 H 1e 4b 7m 91
14 p-ClC6H4CH2 H 1f 4b 7n 91
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a

Reagents and conditions: 1 (1.0 mmol), 2 (1.5 mmol), 4 (1.0 mmol) and solvent (8 mL).

b

Isolated yield based on 1.

Scheme 2. Proposed Mechanism for the Formation of 2-Aminopyridines 6.

Scheme 2

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On the basis of above results, we examined the scope and limitations of the cascade reaction using the cyclic 1,3-dicarbonyl compound 1H-indene-1,3(2H)-dione (Table 4, entries 1–8). The results showed that the different substituent groups of EDAMs 1 usually had a slight effect on the yields. As a result, we can obtain the target compounds 8 with excellent yields (Table 4, entries 1–8).

Table 4. Synthesis of APDs 8a.

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entry R 1 8 yieldb (%)
1 p-CH3OC6H4CH2CH2 1a 8a 89
2 p-CH3C6H4CH2CH2 1b 8b 93
3 C6H5CH2CH2 1c 8c 91
4 m-FC6H4CH2CH2 1d 8d 91
5 o-FC6H4CH2CH2 1e 8e 92
6 p-ClC6H4CH2 1f 8f 92
7 C6H5 1g 8g 90
8 CH3 1h 8h 86
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a

Reagents and conditions: 1 (1.0 mmol), 2 (1.5 mmol), 5 (1.0 mmol), and solvent (8 mL).

b

Isolated yield based on 1.

The chemical structure of all target derivatives (6–8) was fully characterized by infrared (IR) spectroscopy, proton (1H) nuclear magnetic resonance (NMR), carbon-13 (13C) NMR and high-resolution mass spectrometry (HRMS). To further verify the structure of the target products, some of the representative compounds (6g, 7f, and 8b) were separately selected as representative compounds, whose presence was unequivocally confirmed by X-ray diffraction analysis as shown in Figure 2 (CCDC1879680, CCDC1879681, and CCDC1879683).

Figure 2.

Figure 2

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X-ray crystal structures of 6g, 7f, and 8b; ellipsoids are drawn at the 30% probability level.

On the basis of the above experimental results, we propose the mechanism for the formation of the target compounds 6 as outlined in Scheme 2. First, DMF-DMA 2 reacts with 1,3-dicarbonyl compounds 3 to form compounds 9. Next, the α-C of EDAMs 1 serves as the nucleophilic site to attack the carbonyl of compounds 9 through 1,2-addition reaction promoted by the base to produce the intermediates 10. This was followed by the imine-enamine tautomerization to obtain the intermediates 10. Then, intermediates 10 undergo imine-enamine tautomerization and produce the intermediates 11. Afterward, the amino group of intermediates 11 attacks the C=C bond of the intermediates 11 via Michael addition following the loss of one molecule of NH(Me)2 to produce the intermediates 12 promoted by the base. Finally, the intermediate 12 undergoes aromatization and loses one molecule of H2O promoted by heat to give the target compounds 6 (Scheme 2).

However, the proposed mechanism for the formation of the target compounds 7–8 is different from that of compounds 6. Thus, in this work, we also proposed the mechanism for the formation of the target compounds 7 (Scheme 3), as follows. Initially, DMF-DMA 2 is reacted with cyclic 1,3-dicarbonyl compounds 5 to form compounds 13. Next, the α-C of EDAMs 1 serves as the nucleophilic site to attack the C=C bond of compounds 13 through the Michael addition reaction followed by the loss of one molecule of NH(Me)2 promoted by the base to produce the intermediates 14. Then, the intermediates 14 produce the intermediate 15 via imine-enamine tautomerization promoted by the base. Afterward, the intermediates 15 produce intermediates 16 through an intramolecular cyclization reaction. Eventually, the intermediate 16 undergoes aromatization and, promoted by heat, loses one molecule of H2O to give the target compounds 7 (Scheme 3).

Scheme 3. Proposed Mechanism for the Formation of APDs 7.

Scheme 3

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Conclusions

In summary, we have developed a concise method for the regioselective synthesis of novel APDs via a base-promoted three-component cascade reaction of EDAMs 1, DMF-DMA 2, and 1,3-dicarbonyl compounds 3–5. This method has some advantages, such as low-cost, simple operation without step by step isolation and purification, high yields, the diversity of the target compounds, readily accessible building blocks and potential biological activity of the product. Moreover, we found two different mechanisms of the reaction and compared the substrate 3 with 4–5. This is very interesting because the mechanism of formation of the target compound 6 is based on substrate 3. This protocol provides a useful strategy to construct various kinds of 2-aminoheterocycles including 2-aminopyridines, 2-aminopyrroles, 2-aminoquinolines, 2-aminoindoles, and others in the future.

Experimental Section

General Methods

All compounds were fully characterized by spectroscopic data. The NMR spectra were recorded on a Bruker DRX500 & DRX600. Chemical shifts (δ) are expressed in ppm, J values are given in Hz, and deuterated DMSO-d6 & CDCl3 were used as the solvent. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using a KBr pellet. The reactions were monitored by thin layer chromatography using silica gel GF254. The melting points were determined on a XT-4A melting point apparatus and are uncorrected. HRMs were performed on an Agilent LC/Msd TOF instrument.

Materials used were purchased from Adamas-beta Corporation Limited. All chemicals and solvents were used as received without further purification unless otherwise noted. Column chromatography was performed on silica gel (200–300 mesh). EDAMs 1 were prepared according to the literature.41,42

General Procedure for the Synthesis of Compounds 6–8

A 25 mL round bottom flask was charged with 1,3-dicarbonyl compounds 3–5 (1.0 mmol), 1,4-dioxane (8 mL), and DMF-DMA 2 (1.5 mmol). The mixture was reflux for about 0.5 h. Next, EDAMs 1 (1.0 mmol) and a small amount of Cs2CO3 (0.05 mmol) were added to this mixture, and the solution was stirred for about 5–10 h at reflux. Then, the mixture was cooled to room temperature and added to 50 mL of water, followed by extraction with an appropriate amount of ethyl acetate. The organic phase was combined and dried over anhydrous Na2SO4 and then concentrated under reduced pressure and purified by fast column chromatography (with the appropriate proportion of petroleum ether and ethyl acetate). Eventually, the target compounds 6–8 were obtained with yields of 74–93%.

Ethyl 4-methyl-6-((4-methylphenethyl)amino)-5-nitronicotinate (6a)

Yellow solid; mp 74.0 °C; IR (KBr): 3417, 2956, 1602, 1562, 1360, 1293 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.30 (t, J = 7.0 Hz, 3H, CH3), 2.26 (s, 3H, ArCH3), 2.51 (s, 3H, CH3), 2.79–2.81 (m, 2H, CH2), 3.60–3.64 (m, 2H, NCH2), 4.24–4.28 (m, 2H, OCH2), 7.07–7.11 (m, 4H, ArH), 7.68 (s, 1H, CH), 8.70 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 14.5, 15.8, 21.1, 43.6, 34.7, 61.0, 114.0, 129.0, 129.3, 134.1, 135.5, 136.6, 142.7, 151.4, 153.4, 165.2. HRMS (TOF ES+) m/z: [M + H]+ calcd for C18H22N3O3, 344.1605; found, 344.1604.

Ethyl 4-methyl-5-nitro-6-(phenethylamino)nicotinate (6b)

Yellow solid; mp 75.0 °C; IR (KBr): 3454, 2959, 1605, 1555, 1386, 1261 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.31 (t, J = 7.0 Hz, 3H, CH3), 2.41 (s, 3H, CH3), 2.84–2.87 (m, 2H, CH2), 3.63–3.67 (m, 2H, NCH2), 4.24–4.28 (m, 2H, OCH2), 7.18–7.22 (m, 3H, ArH), 7.27–7.30 (m, 2H, ArH), 7.70 (s, 1H, CH) 8.70 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 14.5, 15.8, 35.1, 42.8, 61.0, 114.1, 126.6, 128.8, 129.1, 134.2, 139.7, 142.7, 151.4, 153.4, 165.2. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H20N3O4, 330.1448; found, 330.1449.

Ethyl 6-((3-fluorophenethyl)amino)-4-methyl-5-nitronicotinate (6c)

Yellow solid; mp 77.0 °C; IR (KBr): 3432, 1708, 1602, 1555, 935, 895 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.30 (t, J = 7.0 Hz, 3H, CH3), 2.40 (s, 3H, CH3), 2.87–2.90 (m, 2H, CH2), 3.65–3.69 (m, 2H, NCH2), 4.24–4.28 (m, 2H, OCH2), 7.01–7.05 (m, 3H, Ar), 7.30–7.33 (m, 1H, Ar), 7.68 (s, 1H, CH), 8.69 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 14.5, 15.8, 34.7, 42.4, 61.0, 113.3 (d, J = 20.0 Hz), 114.1, 115.8 (d, J = 20.0 Hz), 125.3 (d, J = 2.5 Hz), 130.6 (d, J = 7.5 Hz), 134.2, 142.7 (d, J = 15.0 Hz), 151.3, 153.3, 161.7, 163.6, 165.2. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H19FN3O4, 348.1354; found, 348.1352.

Ethyl 6-((4-chlorobenzyl)amino)-4-methyl-5-nitronicotinate (6d)

Yellow solid; mp 89 °C; IR (KBr): 3409, 1716, 1601, 1519, 1017, 796 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.26 (t, J = 7.0 Hz, 3H, CH3), 2.4 (s, 3H, CH3), 4.22–4.27 (m, 2H, OCH2), 4.61–4.62 (d, J = 6.0 Hz, 2H, CH2), 7.29–7.31 (m, 2H, ArH), 7.35–7.37 (m, 2H, ArH), 8.23 (s, 1H, CH), 863 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 14.5, 15.8, 43.8, 61.0, 114.7, 128.7, 129.5, 131.8, 134.3, 138.8, 142.7, 151.2, 153.2, 165.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C16H17ClN3O43, 350.0902; found, 350.0899.

Ethyl 6-((4-fluorobenzyl)amino)-4-methyl-5-nitronicotinate (6e)

Yellow solid; mp 111.0 °C; IR (KBr): 3410, 1715, 1651, 1607, 1044, 876 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −116.2; 1H NMR (500 MHz, DMSO-d6): δ 1.29 (t, J = 7.0 Hz, 3H, CH2CH3), 2.41 (s, 3H, COCH3), 4.22–4.27 (m, 2H, OCH2), 4.61–4.62 (m, 2H, CH2), 7.11–7.14 (m, 2H, ArH), 7.31–7.34 (m, 2H, ArH), 8.22 (s, 1H, CH), 8.65 (br, 1H, NH); (d, J = 240 Hz), 165.1; 13C NMR (125 MHz, DMSO-d6): δ 14.5, 15.8, 43.7, 61.0, 114.6, 115.4 (d, J = 21.3 Hz), 129.6 (d, J = 8.8 Hz), 143.3, 135.9 (d, J = 2.5 Hz), 142.7, 151.2, 153.2, 161.6 (d, J = 240.0 Hz), 165.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C16H17FN3O43, 334.1198; found, 334.1195.

1-(6-((4-Methoxyphenethyl)amino)-4-methyl-5-nitropyridin-3-yl)ethanone (6f)

Yellow solid; mp 105.0 °C; IR (KBr): 3339, 1658, 1600, 1525, 1021, 820 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.34 (s, 3H, COCH3), 2.50–2.54 (m, 3H, CH3), 2.78–2.80 (m, 2H, CH2), 3.60–3.64 (m, 2H, NCH2), 3.72 (s, 3H, OCH3), 6.84–6.87 (m, 2H, ArH), 7.12–7.14 (m, 2H, ArH), 7.68 (s, 1H, CH), 8.82 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 15.9, 29.6, 34.3, 43.1, 55.5, 114.3, 121.7, 130.1, 131.6, 134.9, 141.5, 150.8, 154.0, 158.2, 197.4. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H20N3O4, 330.1448; found, 330.1446.

1-(4-Methyl-6-((4-methylphenethyl)amino)-5-nitropyridin-3-yl)ethanone (6g)

Yellow solid; mp 115.5 °C; IR (KBr): 3402, 1671, 1598, 1551, 960, 878 cm–1; 1H NMR (500 MHz, CDCl3): δ 2.33 (S, 3H, ArCH3), 2.55 (s, 3H, CH3), 2.56 (s, 3H, COCH3), 2.89–2.91 (m, 2H, CH2), 3.77–3.81 (m, 2H, NCH2), 6.53 (s, 1H, CH), 7.10–7.12 (m, 4H, ArH), 8.69 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ 17.0, 21.0, 29.3, 35.0, 43.0, 123.4, 128.6, 129.4, 133.6, 135.4, 136.3, 145.4, 151.7, 153.5, 196.9. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H20N3O3, 314.1499; found, 314.1496.

1-(4-Methyl-5-nitro-6-(phenethylamino)pyridin-3-yl)ethanone (6h)

Yellow solid; mp 66 °C; IR (KBr): 3373, 1674, 1665, 1593, 942, 875 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.34 (s, 3H, CH3), 2.50–2.54 (m, 3H, COCH3), 2.85–2.88 (m, 2H, CH2), 3.64–3.68 (m, 2H, NCH2), 7.19–7.23 (m, 3H, ArH), 7.28–7.31 (m, 2H, ArH), 7.70 (s, 1H, CH), 8.82 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 15.9, 29.6, 35.2, 42.8, 121.9, 126.6, 129.0, 129.1, 134.9, 139.8, 141.5, 150.8, 153.9, 197.4. HRMS (TOF ES+) m/z: [M + H]+ calcd for C16H18N3O3, 300.1343; found, 300.1341.

1-(6-((3-Fluorophenethyl)amino)-4-methyl-5-nitropyridin-3-yl)ethanone (6i)

Yellow solid; mp 79.5 °C; IR (KBr): 3411, 1671, 1598, 1551, 960, 878 cm–1; 1H NMR (600 MHz, CDCl3):δ 2.55 (s, 3H, CH3), 2.57 (s, 3H, COCH3), 2.93–2.96 (m, 2H, CH2), 3.81–3.84 (m, 2H, NCH2), 6.62–6.67 (m, 1H, ArH), 6.93–6.95 (m, 2H, ArH), 6.99–7.00 (m, 1H, ArH), 7.27 (s, 1H, CH), 8.70 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ 17.0, 29.3, 35.2, 42.6, 113.6 (d, J = 21.0 Hz), 115.6 (d, J = 21.0 Hz), 123.6, 124.4 (d, J = 3.0 Hz), 130.2 (d, J = 9.0 Hz), 133.7, 141.1 (d, J = 7.5 Hz), 145.4, 151.6, 153.4, 160.3 (d, J = 244.5 Hz), 196.9. HRMS (TOF ES+) m/z: [M + H]+ calcd for C16H17FN3O3, 318.1248; found, 318.1246.

1-(6-((2-Fluorophenethyl)amino)-4-methyl-5-nitropyridin-3-yl)ethanone (6j)

Yellow solid; mp 89.0 °C; IR (KBr): 3410, 1673, 1604, 1525, 949, 830 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −118.7; 1H NMR (500 MHz, DMSO-d6): δ 2.33 (s, 3H, COCH3), 2.51–2.53 (m, 3H, CH3), 2.90–2.92 (m, 2H, CH2), 3.67–3.68 (m, 2H, NCH2), 7.12–7.14 (m, 2H, ArH), 7.25–7.27 (m, 2H, ArH), 7.73 (s, 1H, CH), 8.80 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 15.9, 115.5 (d, J = 22.5 Hz), 121.9, 124.8 (d, J = 3.8 Hz), 126.3 (d, J = 16.0 Hz), 128.8 (d, J = 8.9 Hz), 131.8 (d, J = 3.8 Hz), 134.9, 141.4, 150.8, 153.8, 160.3, 162.2, 197.5. HRMS (TOF ES+) m/z: [M + H]+ calcd for C16H17FN3O3, 318.1248; found, 318.1245.

1-(6-((4-Chlorobenzyl)amino)-4-methyl-5-nitropyridin-3-yl)ethanone (6k)

Yellow solid; mp 148.0 °C; IR (KBr): 3314, 1656, 1600, 1524, 1015, 816 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.35 (s, 3H, COCH3), 2.51 (s, 3H, CH3), 4.62–4.64 (m, 2H, CH2), 7.30–7.32 (m, 2H, ArH), 7.36–7.38 (m, 2H, ArH), 8.24 (s, 1H, CH), 875 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 15.9, 29.6, 43.7, 12.3, 128.7, 129.3, 131.8, 135.0, 138.9, 141.5, 150.6, 153.7, 197.5. HRMS (TOF ES+) m/z: [M + H]+ calcd for C15H15ClN3O3, 320.0796; found, 320.0796.

1-(6-((4-Methylphenethyl)amino)-5-nitro-4-(trifluoromethyl)pyridin-3-yl)ethanone (6l)

Yellow solid; mp 80.0 °C; IR (KBr): 3440, 1617, 1582, 1516, 943, 869 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −68.1, −61.4; 1H NMR (500 MHz, DMSO-d6): δ 2.53 (s, 3H, CH3), 2.79–2.82 (m, 2H, CH2), 3.57–3.61 (m, 2H, NCH2), 7.05–7.11 (m, 4H, ArH), 7.39 (s, 1H, CH), 8.16 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 21.6, 34.2, 43.6, 104.2, 120.6 (d, J = 272.5 Hz), 121.2 (d, J = 273.8 Hz), 124.2, 129.0, 129.4, 130.6, 132.3 (d, J = 35.0 Hz), 135.6, 136.3, 148.4 (d, J = 35.0 Hz), 150.7. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H14F6N3O3, 422.0934; found, 538.2265.

2,2,2-Trifluoro-1-(6-((2-fluorophenethyl)amino)-5-nitro-4-(trifluoromethyl)pyridin-3-yl)ethanone (6m)

Yellow solid; mp 82.0 °C; IR (KBr): 3455, 1624, 1581, 1532, 949, 851 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −61.4, −68.1, −119.0; 1H NMR (500 MHz, DMSO-d6): δ 2.53 (s, 3H, CH3), 2.90–2.93 (m, 2H, CH2), 3.64–3.68 (m, 2H, NCH2), 7.09–7.13 (m, 2H, ArH), 7.22–7.27 (m, 2H, ArH), 7.38 (s, 1H, CH), 8.19 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 28.1, 41.9, 104.2, 115.5 (d, J = 21.3 Hz), 119.0 (d, J = 273.8 Hz), 120.5 (d, J = 273.8 Hz), 123.8, 124.6 (d, J = 25.0 Hz), 126.0, 128.8 (d, J = 8.8 Hz), 130.6, 132.3 (d, J = 35.0 Hz), 148.4 (d, J = 35.0 Hz), 150.7, 160.3, 162.2. HRMS (TOF ES+) m/z: [M + H]+ calcd for C16H11F7N3O3, 426.0683 found, 538.2265.

(6-((4-Chlorobenzyl)amino)-5-nitro-4-(trifluoromethyl)pyridin-3-yl)(phenyl)methanone (6n)

Yellow solid; mp 102.0 °C; IR (KBr): 3421, 1619, 1565, 1016, 855 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 4.73–4.74 (m, 2H, NCH2), 7.37–7.41 (m, 4H, ArH), 7.42–7.49 (m, 3H, ArH), 7.51–7.57 (m, 1H, ArH), 8.05 (s, 1H, CH), 8.43 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 44.3 (d, J = 31.3 Hz), 110.3, 121.1 (d, J = 273.8 Hz), 127.8 (d, J = 23.8 Hz), 128.6 (d, J = 12.5 Hz), 129.4 (d, J = 23.4 Hz), 130.2 (d, J = 15.0 Hz), 131.5, 132.0, 133.6, 134.7, 138.6, 139.1, 145.9, 146.7 (d, J = 35.0 Hz), 150.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C20H14ClF3N3O3, 436.0670; found, 436.0673.

(5-Nitro-6-(phenethylamino)-4-phenylpyridin-3-yl)(phenyl)methanone (6o)

Yellow solid; mp 133.0 °C; IR (KBr): 3424, 1654, 1600, 1588, 982, 959 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.91–2.94 (m, 2H, CH2), 3.71–3.73 (m, 2H, NCH2), 7.11–7.13 (m, 2H, ArH), 7.22–7.24 (m, 4H, ArH), 7.26–7.27 (m, 2H, ArH), 7.29–7.31 (m, 2H, ArH), 7.35–7.38 (m, 2H, ArH), 7.49–7.53 (m, 1H, ArH), 7.58–7.60 (m, 2H, ArH), 7.75–7.76 (m, 1H, CH), 8.39 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 35.2, 43.0, 123.7, 126.6, 128.3, 128.7, 128.9, 128.9, 129.1, 129.1, 129.1, 132.1, 133.58 (d, J = 25.0 Hz), 137.8, 139.8, 143.7, 150.9, 151.7, 193.8. HRMS (TOF ES+) m/z: [M + H]+ calcd for C26H22N3O3, 424.1656; found, 424.1653.

(6-((2-Fluorophenethyl)amino)-5-nitro-4-phenylpyridin-3-yl)(phenyl)methanone (6p)

Yellow solid; mp 99.6 °C; IR (KBr): 3406, 1654, 1592, 1513, 983, 805 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −118.5 Hz; 1H NMR (500 MHz, DMSO-d6): δ 2.95–2.98 (m, 2H, CH2), 3.72–3.76 (m, 2H, NCH2), 7.10–7.17 (m, 4H, ArH), 7.23–7.24 (m, 3H, ArH), 7.27–7.29 (m, 1H, ArH), 7.31–7.50 (m, 3H, ArH), 7.50–7.51 (m, 3H, ArH), 7.57–7.59 (m, 2H, ArH), 7.78 (s, 1H, CH), 8.36 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 28.7, 41.6, 115.5 (d, J = 21.3 Hz), 123.7, 124.8, 126.4, 127.8, 128.3, 128.8, 128.8, 129.2, 129.9, 131.2, 131.8 (d, J = 5.0 Hz), 133.5 (d, J = 18.8 Hz), 137.8, 143.6, 150.9, 151.6, 160.3, 162.2, 193.8. HRMS (TOF ES+) m/z: [M + H]+ calcd for C26H21FN3O3, 442.1561; found, 442.1558.

2-((3-Methoxyphenethyl)amino)-7,7-dimethyl-3-nitro-7,8-dihydroquinolin-5(6H)-one (7a)

Yellow solid; mp 92.0 °C; IR (KBr): 3325, 1681, 1666, 1592, 1036, 818 cm–1; 1H NMR (500 MHz, CDCl3): δ 1.00 (s, 6H, CCH3, CCH3), 2.48–2.51 (m, 2H, COCH2), 2.86–2.89 (m, 4H, CCH2, CH2), 3.71 (s, 3H, OCH3), 3.81–3.85 (m, 2H, NCH2), 6.85–6.87 (m, 2H, ArH), 7.17–7.18 (m, 2H, ArH), 8.64 (s, 1H, CH), 8.92 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ 28.3, 32.7, 34.4, 43.4, 46.6, 51.2, 55.5, 114.4, 117.2, 127.5, 130.2, 131.4, 133.8, 153.1, 158.3, 169.6, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C20H24N3O4, 370.1761; found, 370.1762.

7,7-Dimethyl-2-((4-methylphenethyl)amino)-3-nitro-7,8-dihydroquinolin-5(6H)-one (7b)

Yellow solid; mp 107.5 °C; IR (KBr): 3392, 1678, 1517, 958, 811 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.02 (s, 6H, CCH3, CCH3), 2.26 (s, 3H, CH3), 2.48–2.51 (m, 2H, COCH2), 2.86–2.90 (m, 4H, CH2, CCH2), 3.82–3.86 (m, 2H, NCH2), 7.10–7.11 (m, 1H, ArH), 7.14–7.16 (m, 2H, ArH), 8.63 (s, 1H, CH), 8.93 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 21.1, 28.2, 32.6, 34.8, 43.2, 46.5, 51.1, 117.1, 127.5, 129.0, 129.4, 133.7, 135.6, 136.4, 153.0, 169.5, 195.0. HRMS (TOF ES+) m/z: [M + H]+ calcd for C20H14N3O3, 354.1812; found, 354.1810.

7,7-Dimethyl-3-nitro-2-(phenethylamino)-7,8-dihydroquinolin-5(6H)-one (7c)

Yellow solid; mp 172.0 °C; IR (KBr): 3392, 1679, 1600, 1525, 1070, 857 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.03 (s, 6H, CH3, CH3), 2.48–2.50 (m, 2H, COCH2), 2.87 (s, 2H, CCH2), 2.93–2.96 (m, 2H, CH2), 3.85–3.89 (m, 2H, NCH2), 7.21–7.22 (m, 1H, ArH), 7.28–7.32 (m, 3H, ArH), 8.64 (s, 1H, CH), 8.95 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 28.3, 32.7, 35.2, 43.1, 46.5, 51.2, 117.2, 126.7, 127.5, 128.9, 129.2, 133.7, 139.5, 153.0, 169.5, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C19H22N3O3, 340.1656; found, 340.1655.

2-((3-Fluorophenethyl)amino)-7,7-dimethyl-3-nitro-7,8-dihydroquinolin-5(6H)-one (7d)

Yellow solid; mp 165.0 °C; IR (KBr): 3395, 1679, 16 001, 1525, 941, 866 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −113.6; 1H NMR (500 MHz, DMSO-d6): δ 1.02 (s, 6H, CCH3, CCH3), 2.48–2.51 (m, 2H, COCH2), 2.86 (s, 2H, CCH2), 2.96–2.99 (m, 2H, CH2), 3.88–3.90 (m, 2H, NCH2), 7.01–7.03 (m, 1H, ArH), 7.09–7.13 (m, 2H, ArH), 7.32–7.34 (m, 1H, ArH), 8.64 (s, 1H, CH), 8.95 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 28.2, 32.6, 34.9, 42.6, 46.5, 51.1, 113.5 (d, J = 21.3 Hz), 115.9 (d, J = 20 Hz), 117.2, 125.4 (d, J = 1.25 Hz), 127.5, 130.6 (d, J = 8.75 Hz), 133.7, 142.6 (d, J = 7.5 Hz), 153.0, 162.7(d, J = 241.3 Hz), 169.4, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C19H21FN3O3, 358.1561; found, 358.1563.

2-((2-Fluorophenethyl)amino)-7,7-dimethyl-3-nitro-7,8-dihydroquinolin-5(6H)-one (7e)

Yellow solid; mp 187.0 °C; IR (KBr): 3385, 1680, 1601, 957, 859 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.01 (s, 3H, CH3), 1.02 (s,3H, CH3), 2.47–2.51 (m, 2H, COCH2), 2.82–2.83 (s, 2H, CH2), 2.99 (s, 2H, CCH2), 3.88–3.90 (m, 2H, NCH2), 7.10–7.16 (m, 2H, ArH), 7.24–7.25 (m, 1H, ArH), 7.30–7.32 (m, 1H, ArH), 8.63 (s, 1H, CH), 9.01 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 28.3, 28.7, 32.6, 41.6, 46.4, 51.2, 115.4, 115.6, 117.2, 124.8, 126.2, 126.3, 127.5, 128.9, 131.8, 133.7, 153.1, 169.4, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C19H21FN3O3, 358.1561; found, 358.1563.

2-((4-Chlorobenzyl)amino)-7,7-dimethyl-3-nitro-7,8-dihydroquinolin-5(6H)-one (7f)

Yellow solid; mp 162.5 °C; IR (KBr): 3385, 1682, 1592, 1574, 977, 853 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.00 (s, 6H, CCH3, CCH3), 2.47–2.51 (m, 2H, COCH2), 2.83 (s, 2H, CCH2), 4.81–4.82 (m, 2H, CH2), 7.36–7.383 (m, 2H, ArH), 7.43–7.44 (m, 2H, ArH), 8.66 (s, 1H, CH), 9.44 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 28.2, 32.7, 44.2, 46.4, 51.1, 117.5, 127.8, 128.7, 128.7, 130.1, 132.0, 133.7, 155.8, 169.3, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C18H19ClN3O3, 360.1109, found, 360.1109.

2-((4-Fluorobenzyl)amino)-7,7-dimethyl-3-nitro-7,8-dihydroquinolin-5(6H)-one (7g)

Yellow solid; mp 124.0 °C; IR (KBr): 3379, 1683, 1591, 1502, 974, 852 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −115.8; 1H NMR (500 MHz, DMSO-d6): δ 1.00 (s, 6H, CCH3, CCH3), 2.0 (s, 2H, COCH2), 2.85 (s, 2H, CCH2), 4.81–4.82 (m, 2H, CH2), 7.12–7.16 (m, 2H, ArH), 7.45–7.48 (m, 2H, ArH), 8.66 (s, 1H, CH), 9.42 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 28.2, 32.7, 44.1, 46.4, 51.1, 115.4 (d, J = 21.3 Hz), 117.5, 127.8, 130.3 (d, J = 8.8 Hz), 133.7, 135.5, 152.8, 161.7 (d, J = 241.3 Hz), 169.3, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C18H19FN3O3, 344.1405; found, 344.1404.

7,7-Dimethyl-3-nitro-2-(phenylamino)-7,8-dihydroquinolin-5(6H)-one (7h)

Yellow solid; mp 85 °C; IR (KBr): 3438, 1735, 16 311, 1461, 1190, 840 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 1.03 (s, 6H, CCH3, CCH3), 2.89 (s, 2H, COCH2), 3.35 (s, 2H, CCH2), 7.22 (s, 1H, ArH), 7.42 (s, 2H, ArH), 7.74 (s, 2H, ArH), 8.73 (s, 1H, CH), 10.32 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 28.2, 32.8, 46.2, 51.1, 119.0, 123.6, 125.5, 128.7, 129.2, 133.8, 138.1, 150.8, 168.9, 195.2. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H17N3O3, 312.1343; found, 312.1338.

2-((4-Methoxyphenethyl)amino)-3-nitro-7,8-dihydroquinolin-5(6H)-one (7i)

Yellow solid; mp 129.0 °C; IR (KBr): 3365, 1672, 1603, 1512, 914, 809 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.02–2.07 (m, 2H, CH2), 2.55–2.58 (m, 2H, COCH2), 2.85–2.88 (m, 2H, ArCH2), 2.92–2.95 (m, 2H, CCH2), 3.72 (s, 2H, OCH3), 3.78–3.82 (m, 2H, NCH2), 6.85–6.87 (m, 2H, ArH), 7.17–7.19 (m, 2H, ArH), 8.63 (s, 1H, CH), 8.89 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 21.1, 33.1, 34.3, 37.8, 43.3, 37.8, 43.3, 55.5, 114.3, 118.2, 127.5, 130.1, 131.4, 134.1, 152.6, 158.3, 170.8, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C18H20N3O4, 342.1448; found, 342.1451.

2-((3-Methylphenethyl)amino)-3-nitro-7,8-dihydroquinolin-5(6H)-one (7j)

Yellow solid; mp 122.0 °C; IR (KBr): 3361, 1669, 1598, 1514, 954, 844 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.01–2.07 (m, 2H, CH2CH2CH2), 2.26 (S, 3H, CH3), 2.50 (S, 2H, COCH2), 2.87–2.90 (m, 2H, CH2), 2.94–2.96 (m, 2H, CCH2), 3.81–3.85 (m, 2H, NCH2), 7.10–7.16 (m, 4H, ArH), 8.65 (s, 1H, CH), 8.91 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ 21.0, 21.2, 33.2, 35.0, 37.9, 43.1, 118.7, 127.8, 128.6, 129.4, 135.1, 135.4, 136.3, 152.7, 170.3, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C18H20N3O3, 326.1499; found, 326.1501.

3-Nitro-2-(phenethylamino)-7,8-dihydroquinolin-5(6H)-one (7k)

Yellow solid; mp 130.0 °C; IR (KBr): 3374, 1671, 1598, 1572, 1134, 890 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.02–2.06 (m, 2H, CH2), 2.56–2.57 (m, 2H, COCH2), 2.93–2.94 (m, 4H, ArCH2, CCH2), 3.84–3.85 (m, 2H, NCH2), 7.21–7.22 (m, 1H, ArH), 7.27–7.32 (m, 4H, ArH), 8.63 (s, 1H, CH), 8.93 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 21.1, 33.1, 35.2, 37.8, 43.1, 118.2, 126.7, 127.6, 128.9, 129.2, 134.1, 139.6, 152.6, 170.8, 195.2. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H18N3O3, 312.1343; found, 312.1342.

2-((3-Fluorophenethyl)amino)-3-nitro-7,8-dihydroquinolin-5 (6H)-one (7l)

Yellow solid; mp 149.0 °C; IR (KBr): 3376, 1677, 1603, 1587, 1045, 907 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −113.6; 1H NMR (500 MHz, DMSO-d6): δ 2.02–2.07 (m, 2H, CH2), 2.56–2.58 (t, J = 6.5 Hz, 2H, COCH2), 2.93–2.98 (m, 4H, ArCH2, CCH2), 3.85–3.89 (m, 2H, NCH2), 7.09–7.13 (m, 2H, ArH), 7.31–7.36 (m, 1H, ArH), 8.64 (s, 1H, CH), 8.94 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 21.2, 33.1, 34.8, 37.8, 42.7, 113.5 (d, J = 20.0 Hz), 115.9 (d, J = 21.3 Hz), 118.3, 125.4 (d, J = 2.5 Hz), 127.6, 130.7 (d, J = 7.5 Hz), 134.1, 142.6 (d, J = 7.5 Hz), 152.6, 162.7 (d, J = 242.5 Hz), 170.8, 195.2. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H17FN3O3 [M + H]+, 330.1248; found, 330.1241.

2-((2-Fluorophenethyl)amino)-3-nitro-7,8-dihydroquinolin-5 (6H)-one (7m)

Yellow solid; mp 146.0 °C; IR (KBr): 3373, 1672, 1600, 1087, 909 cm–1; 1H NMR (500 MHz, CDCl3): δ 2.11–2.17 (m, 2H, CH2), 2.62–2.64 (m, 2H, ArCH2), 2.96–2.98 (m, 2H, COCH2), 3.03–3.06 (m, 2H, CCH2), 3.94–3.98 (m, 2H, NCH2), 7.03–7.10 (m, 2H, ArH), 7.20–7.26 (m, 2H, ArH), 8.50 (s, 1H, CH), 8.98 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ 21.2, 29.1, 33.2, 38.0, 41.7, 115.5 (d, J = 22.5 Hz), 118.7, 124.3, 125.4 (d, J = 15.0 Hz), 127.8, 128.6 (d, J = 7.5 Hz), 131.1 (d, J = 3.8 Hz), 135.0, 152.9, 161.4 (d, J = 243.8 Hz), 170.3, 195.2. HRMS (TOF ES+) m/z: [M + H]+ calcd for C17H17FN3O3, 330.1248; found, 330.1248.

2-((4-Chlorobenzyl)amino)-3-nitro-7,8-dihydroquinolin-5(6H)-one (7n)

Yellow solid; mp 109.1 °C; IR (KBr)3359, 1675, 1594, 1519, 954, 840 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.00–2.05 (m, 2H, CH2), 2.51–2.58 (m, 2H, COCH2), 2.88–2.91 (m, 2H, CCH2), 4.80–4.81 (m, 2H, NCH2), 7.36–7.37 (m, 2H, ArH), 7.42–7.44 (m, 2H, ArH), 8.66 (s, 1H, CH), 9.94 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 21.1, 33.0, 37.7, 44.2, 118.6, 127.9, 128.7, 130.1, 132.0, 134.1, 138.4, 152.4, 170.6, 195.1. HRMS (TOF ES+) m/z: [M + H]+ calcd for C16H15ClN3O3, 332.0796; found, 332.0797.

2-((4-Methoxyphenethyl)amino)-3-nitro-5H-indeno[1,2-b]pyridin-5-one (8a)

Yellow solid; mp 192.5 °C; IR (KBr): 3367, 1705, 1617, 1595, 997, 825 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 2.93–2.96 (m, 2H, CH2), 3.69 (s, 3H, OCH3), 3.96–4.00 (m, 2H, NCH2), 6.86–6.88 (m, 2H, ArH), 7.24–7.25 (m, 2H, ArH), 7.67–7.70 (m, 1H, ArH), 7.75–7.81 (m, 2H, ArH), 7.91–7.92 (m, 1H, ArH), 8.47 (s, 1H, CH), 9.45 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ 34.7, 43.6, 55.3, 114.3, 117.5, 122.1, 123.8, 129.7, 130.3, 131.3, 132.8, 134.6, 138.3, 141.1, 156.0, 157.8, 158.6, 168.0, 170.0. HRMS (TOF ES+) m/z: [M + H]+ calcd for C21H18N3O4, 376.1292; found, 376.1292.

2-((4-Methylphenethyl)amino)-3-nitro-5H-indeno[1,2-b]pyridin-5-one (8b)

Yellow solid; mp 197.0 °C; IR (KBr): 3356, 1708, 1616, 1585, 997, 767 cm–1; 1H NMR (600 MHz, CDCl3): δ 2.33 (s, 3H, CH3), 3.02–3.04 (m, 2H, CH2), 4.05–4.09 (m, 2H, NCH2), 7.15–7.20 (m, 3H, ArH), 7.24–7.28 (m, 1H, ArH), 7.55–7.58 (m, 1H, ArH), 7.64–7.66 (m, 1H, ArH), 7.76–7.77 (m, 1H, ArH), 7.87–7.88 (m, 1H, ArH), 8.66 (s, 1H, CH), 9.08 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ 21.0, 35.1, 43.5, 117.5, 122.1, 123.8, 126.9, 128.6, 129.5, 131.2, 132.8, 134.6, 135.2, 136.5, 138.3, 141.1, 155.9, 170.0, 188.7. HRMS (TOF ES+) m/z: [M + H]+ calcd for C21H18N3O3, 360.1343; found, 360.1343.

3-Nitro-2-(phenethylamino)-5H-indeno[1,2-b]pyridin-5-one (8c)

Yellow solid; mp 168.0 °C; IR (KBr): 3360, 1711, 1622, 1596, 1045, 803 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 3.00–3.02 (m, 2H, CH2), 3.96–4.00 (m, 2H, NCH2), 7.21–7.24 (m, 1H, ArH), 7.33–7.34 (m, 4H, ArH), 7.64–7.67 (m, 1H, ArH), 7.71–7.72 (m, 1H, ArH), 7.74–7.78 (m, 1H, ArH), 7.85–7.86 (m, 1H, ArH), 8.40 (s, 1H, CH), 8.51 (s, 1H, CH), 9.44 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 35.4, 43.6, 116.7, 122.3, 123.8, 126.8, 126.8, 129.0, 129.2, 131.0, 133.6, 135.6, 138.0, 139.4, 140.8, 155.6, 169.5, 188.3. HRMS (TOF ES+) m/z: [M + H]+ calcd for C20H16N3O3, 346.1186; found, 346.1186.

2-((3-Fluorophenethyl)amino)-3-nitro-5H-indeno[1,2-b]pyridin-5-one (8d)

Yellow solid; mp 183.5 °C; IR (KBr): 3337, 1703, 1616, 1583, 997, 936 cm–1; 19F NMR (470 MHz, DMSO-d6): δ −113.3; 1H NMR (500 MHz, DMSO-d6): δ 3.06–3.09 (m, 2H, CH2), 4.06–4.10 (m, 2H, NCH2), 6.93–6.96 (m, 1H, ArH), 7.08–7.13 (m, 2H, ArH), 7.30–7.34 (m, 1H, ArH), 7.61–7.64 (m, 1H, ArH), 7.71–7.74 (m, 2H, ArH), 8.04 (s, 1H, ArH), 8.51 (s, 1H, CH), 9.37 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ 35.4, 43.0, 113.8 (d, J = 21.3 Hz), 115.6 (d, J = 20.0 Hz), 117.6, 122.1, 123.8, 124.4, 127.0, 130.3 (d, J = 8.8 Hz), 131.2, 132.9, 134.7, 138.2, 140.9 (d, J = 23.8 Hz), 115.9, 162.1, 164.1, 170.0, 188.6. HRMS (TOF ES+) m/z: [M + H]+ calcd for C20H15FN3O3, 364.1092; found, 364.1094.

2-((2-Fluorophenethyl)amino)-3-nitro-5H-indeno[1,2-b]pyridin-5-one (8e)

Yellow solid; mp 195.0 °C; IR (KBr): 3338, 1704, 1617, 1586, 956, 904 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 3.05–3.08 (m, 2H, CH2), 4.00–4.04 (m, 2H, NCH2), 7.11–7.14 (m, 2H, ArH), 7.15–7.25 (m, 1H, ArH), 7.35–7.38 (m, 1H, ArH), 7.65–7.66 (m, 1H, ArH), 7.68–7.69 (m, 1H, ArH), 7.78–7.80 (m, 1H, ArH), 7.81–7.87 (m, 1H, ArH), 8.44 (s, 1H, CH), 9.53 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ 29.4, 42.0, 115.5, 115.6, 117.6, 122.1, 123.8, 124.4, 125.3 (d, J = 16.5 Hz), 126.9, 128.7 (d, J = 7.5 Hz), 131.2 (d, J = 6.0 Hz), 132.8, 134.6, 138.2, 141.1, 156.0, 162.3, 169.9, 188.7. HRMS (TOF ES+) m/z: [M + H]+ calcd for C20H15FN3O3, 364.1092; found, 364.1094.

2-((4-Chlorobenzyl)amino)-3-nitro-5H-indeno[1, 2-b]pyridin-5-one (8f)

Yellow solid; mp 228.0 °C; IR (KBr): 3368, 1735, 1654, 1618, 942, 836 cm–1; 1H NMR (500 MHz, DMSO-d6): δ 4.94–4.96 (m, 2H, CH2), 7.38–7.40 (m, 2H, ArH), 7.54–7.55 (m, 2H, ArH), 7.66–7.68 (m, 1H, ArH), 7.73–7.78 (m, 2H, ArH), 7.86–7.88 (m, 1H, ArH), 8.47 (s, 1H, CH), 8.94 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ 45.1, 118.1, 122.1, 123.9, 127.2, 129.1, 129.2, 131.3, 132.9, 133.8, 134.8, 135.9, 138.2, 141.0, 155.7, 170.0, 188.5. HRMS (TOF ES+) m/z: [M + H]+ calcd for C19H13ClN3O3, 366.0640; found, 5366.0641.

3-Nitro-2-(phenylamino)-5H-indeno[1,2-b]pyridin-5-one (8g)

Yellow solid; mp 176.6 °C; IR (KBr): 3378, 1730, 1604, 1530, 1285.36, 1130.35 cm–1; 1H NMR (600 MHz, CDCl3): δ 7.26–7.29 (m, 1H, ArH), 7.45–7.48 (m, 2H, ArH), 7.55–7.58 (m, 1H, ArH), 7.62–7.64 (m, 1H, ArH), 7.76–7.81 (m, 1H, ArH), 8.74 (s, 1H, CH), 10.89 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ 119.2, 122.4, 122.9, 123.9, 125.8, 127.3, 129.1, 131.4, 133.0, 134.8, 137.1, 138.0, 140.9, 153.5, 169.8, 188.4. HRMS (TOF ES+) m/z: [M + H]+ calcd for C18H12N3O3, 318.0873; found, 318.0873.

2-(Methylamino)-3-nitro-5H-indeno[1,2-b]pyridin-5-one (8h)

Yellow solid; mp 121.8 °C; IR (KBr): 3378, 1730, 1604, 1530, 1285, 1130 cm–1; 1H NMR (600 MHz, DMSO): δ 3.25–3.28 (d, 3H, CH3), 7.66–7.68 (m, 1H, ArH), 7.73–7.77 (m, 2H, ArH), 7.87–7.88 (m, 1H, ArH), 8.44 (s, 1H, CH), 9.41 (br, 1H, NH); 13C NMR (150 MHz, DMSO): δ 29.5, 116.4, 122.4, 123.8, 127.2, 130.9, 133.6, 135.6, 138.1, 140.9, 156.1, 169.6, 188.5. HRMS (TOF ES+) m/z: calcd for C13H10N3O3, 256.0717; found, 256.0717.

Acknowledgments

This work was supported by the Program for Changjiang Scholars and Innovative Research Team in University (IRT17R94), the National Natural Science Foundation of China (nos. 21662042, 81760621, 21362042, U1202221), the Natural Science Foundation of Yunnan Province (2017FA003), the High-Level Talents Introduction Plan of Yunnan Province, Donglu Schloars of Yunnan University, Excellent Young Talents of Yunnan University (XT412003). We also thank Dr. Rong Huang of Advanced Analysis and Measurement Center of Yunnan University for helpful testing the NMR.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b03284.

  • Spectroscopic and analytical data as well as the original copy of 1H and 13C NMR spectra of all new compounds (PDF)

  • X-ray crystallographic data (CIF file) of compound 6g (CCDC 1879680), 7f (CCDC 1879681) and 8b (CCDC 1879683) (CIF)

  • Crystallographic data (CIF)

  • Crystallographic data (CIF)

The authors declare no competing financial interest.

Supplementary Material

ao8b03284_si_001.pdf (9MB, pdf)
ao8b03284_si_002.cif (317.9KB, cif)
ao8b03284_si_003.cif (366.9KB, cif)
ao8b03284_si_004.cif (673.7KB, cif)

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Associated Data

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Supplementary Materials

ao8b03284_si_001.pdf (9MB, pdf)
ao8b03284_si_002.cif (317.9KB, cif)
ao8b03284_si_003.cif (366.9KB, cif)
ao8b03284_si_004.cif (673.7KB, cif)

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