Cascade Reaction of 1,1-Enediamines with 2-Benzylidene-1H-indene-1,3(2H)-diones: Selective Synthesis of Indenodihydropyridine and Indenopyridine Compounds.

A concise and environmentally friendly route for the synthesis of diverse indenodihydropyridines (3) via a cascade reaction of 1,1-eneamines (1) with benzylidene-1H-indene-1,3(2H)-diones (BIDs) (2) in ethanol media was developed. The targeted compounds were efficiently obtained by only filtration without any further post-treatment. In the one-step cascade reaction, C-C and C-N bonds were constructed. In addition, when 1,4-dioxane was used as a solvent and the mixture of 1,1-eneamines (1) was refluxed with benzylidene-1H-indene-1,3(2H)-diones (BIDs) (2) for about 12 h, indenopyridine compounds (4) were produced. Two kinds of indenopyridine derivatives 3-4 resulted from alternative solvents and temperatures. The reaction had the following features: mild temperature, atom economy, high yields, and potential biological activity of the product.

Introduction

Group-assisted purification[1,2] allows for the synthesis of diverse compounds without using traditional purification technologin class="Chemical">es such as column chromatography. The focus of this technology is the search for eco-friendly reagents and reactions to reduce the waste generated from silica and solvents, particularly toxic solvents. The aim is the development of an environmentally friendly and efficient method to construct C–C and C–N bonds for the synthesis of N-containing heterocyclic compounds.[3−5]

Pyridine derivativn class="Chemical">es are vital N-containing heterocyclic compounds that are widely found in natural products and synthetic drugs.[6−22] Consequently, more pyridine derivatives have been designed and synthesized.[6−22] Among them, 1,4-dihydropyridines and pyridine compounds have interesting biological activity. For example, 1,4-dihdropyridines have various biological activities and are widely used as drugs including calcium channel blockers (for example, nifedipine, nimodipine, mebudipine, and felodipine, Figure ),[6−8] mineralocorticoid receptor antagonists,[8] sirtuin activators and inhibitors,[9] transforming growth factor-β signaling inhibitors,[10] CB2 receptor agonists,[11] cardiodepressant activators,[12] and Alzheimer’s disease medications.[13,14] Similarly, the pyridines have broad-spectrum biological activity such as anti-human immunodeficiency virus,[15] antitumor,[16−18] anti-inflammatory,[19] antifungal,[20] antihistamine,[21] antidepressant, antiarthritic, antidiabetic, antiglaucoma,[22] and antiprion.

Figure 1

Biological activity of dihydropyridines.

The indenonucleolus is a core unit of various natural alkaloids like n class="Chemical">onychnine and polyfothine (Figure ).[23,24] Combining the structure of pyridines or 1,4-dihydropyridines with indenones in one molecule is especially important for novel pharmaceutical molecules. Consequently, various indenopyridines have been constructed;[25−32] these compounds (Figure ) are important pharmaceuticals and bioactive natural products. They have wide-spectrum biological activities and are mainly used as antitumor or antiproliferative drugs[25−29] (Figure ; TAS-103,[25] 6-aryl-indeno[1,2-c]quinolones,[26] compounds A[28] and B[29]). However, the molecules of 1,4-dihydropyridines combined with indenones are not extensively used. Therefore, the development of effective methods for the rapid preparation of the indenodihydropyridine (IDDP) library is urgent.

Figure 2

Biological activity of indenopyridine derivatives and the targeted compounds 3–4.

1,1-Enediamines (n class="Chemical">EDAMs) are fascinating and versatile building blocks that are widely used to synthesize various fused heterocyclic compounds.[33−50] We have used EDAMs as bisnucleophilic reagents to react with isatins via a cascade reaction for the synthesis of indenopyridine derivatives[33,34] (Scheme ).[33] Other researchers have used a diversity of enamines as substrates for the synthesis of various indenopyridine derivatives through cascade reactions.[35−38] Based on the importance of indenopyridine derivatives, we explored the cascade of EDAMs for synthesis of indenopyridine derivatives including indenopyridines and IDDPs.

Scheme 1

Methods for the Construction of Indenopyridine Derivatives

In this article, we describe a cascade strategy for the convergent synthesis of a kind of IDDPs (3) and a type of indenopyridines (4) through alternative solvents and temperatures. We realize that one protocol for synthesis of two kinds of heterocycles kills two birds with one stone. The reaction is particularly attractive due to the following features: eco-friendliness (EtOH as a solvent and without column chromatography for compound 3; air as an oxidant to obtain compound 4), mild temperature, atom economy, high yields, and potential biological activity of the product.

Results and Discussion

To obtain the indenopyridine derivativn class="Chemical">es, we searched for the optimal reaction conditions that were based on the model reaction of the reaction of EDAM 1a with benzylidene-1H-indene-1,3(2H)-dione (BID) 2a. Solvents including acetone, ethanol, and 1,4-dioxane (Table , entries 1–3) were screened. The results showed that the reaction could proceed in ethanol at room temperature (r.t.) without any promoters (Table , entry 2) and give the target compound 3a with 50% yield. With the same solvent (ethanol) and increased reflux temperature, the reaction produced compound 3a with a good yield (91%) (Table , entry 5). Using 1,4-dioxane as a solvent and refluxing for about 12 h resulted in the target compound 4a with 90% yield (Table , entry 6). Different bases such as Cs2CO3, t-BuOK, and Et3N, and acid promoter HOAc were added to the reaction mixture. The results showed that the three bases could not promote the yield of the cascade reaction. Among them, Cs2CO3 and t-BuOK made the reaction more complicated due to their stronger alkalinities (Table , entries 7 and 8). The promoters Et3N and HOAc slightly decreased the yield of the reaction (Table , entry 5 vs 9 and 10). Different promoters including Cs2CO3, t-BuOK, and Et3N and HOAc were added to 1,4-dioxane and refluxed for 12 h. The promoters Cs2CO3, t-BuOK, and Et3N also slightly decreased the yield of the reaction (Table , entry 5 vs 11–13). When HOAc was used as a promoter, the reaction produced the indenopyridine 4a with 60% yield (Table , entry 14). Finally, the reaction time was screened and it was revealed that the cascade reaction for synthesis of 3a in ethanol and refluxing for about 6 h led to the best yield (Table , entry 5 vs 15). The results showed that the optimal reaction for synthesis of IDDP 3a is the mixture in an environmentally friendly solvent and refluxing for about 6 h without any promoter. The optimal reaction for production of the indenopyridine 4a was 1,4-dioxane used as a solvent and refluxing for 12 h without any promoter (Table , entry 6 vs 16).

Table 1

Optimization of the Reaction Conditionsa

entry	solvent	catalyst	T (°C)	time (h)	3a/yield (%)b	4a/yield (%)b
1	acetone	−	r.t.	12	−	−
2	EtOH	−	r.t.	12	50	−
3	1,4-dioxane	−	r.t.	12	−	−
4	acetone	−	reflux	12	complex	complex
5	EtOH	−	reflux	12	91	−
6	1,4-dioxane	−	reflux	12	−	90
7	EtOH	Cs2CO3	reflux	12	complex	complex
8	EtOH	t-BuOK	reflux	12	complex	complex
9	EtOH	Et3N	reflux	12	85	trace
10	EtOH	HOAc	reflux	12	80	trace
11	1,4-dioxane	Cs2CO3	reflux	12	complex	complex
12	1,4-dioxane	t-BuOK	reflux	12	complex	complex
13	1,4-dioxane	Et3N	reflux	12	88	trace
14	1,4-dioxane	HOAc	reflux	12	trace	60
15	EtOH	−	reflux	6	93	−
16	1,4-dioxane	−	reflux	6	trace	82

Reaction conditions: EDAM 1a (1.1 mmol) and BID 2a (1.0 mmol) were dissolved in a solvent (20 mL).

Isolated yield based on BID 2a.

Based on the optimal reaction conditions, we further investigated the scope and generality of the cascade reaction of the n class="Chemical">EDAMs 1 with BIDs 2. Different substituted EDAMs 1 and other BIDs 2 were used in this protocol (Table , entries 1–21). The results revealed that the substituted group on EDAMs 1 has only a slight influence on the yield. Similarly, the substituted groups of BIDs 2 also had slight effects on the yields of the reaction. We concluded that different EDAMs 1 and a variety of BIDs 2 are good substrates for this cascade reaction and produce the target compounds 3a–u with excellent yields (90–98%).

Table 2

Synthesis of Indenodihydropyridines (IDDPs) 3a

entry	R	R′	3	yield (%)b
1	p-FC6H4CH2	F	3a	93
2	p-FC6H4CH2	Cl	3b	93
3	p-FC6H4CH2	Me	3c	97
4	p-ClC6H4CH2	Cl	3d	98
5	p-ClC6H4	H	3e	97
6	p-ClC6H4CH2	H	3f	96
7	p-ClC6H4CH2	Me	3g	92
8	p-ClC6H4	OMe	3h	94
9	p-ClC6H4CH2CH2	OMe	3i	95
10	C6H5CH2CH2	F	3j	93
11	C6H5	Cl	3k	91
12	C6H5CH2	Cl	3l	92
13	C6H5CH2CH2	Cl	3m	92
14	C6H5CH2CH2	H	3n	94
15	C6H5CH2	Me	3o	96
16	C6H5	OMe	3p	90
17	C6H5CH2CH2	OMe	3q	95
18	p-OMeC6H4CH2CH2	F	3r	93
19	p-OMeC6H4CH2CH2	Cl	3s	93
20	p-OMeC6H4CH2CH2	H	3t	90
21	p-OMeC6H4CH2CH2	Me	3u	93

Reaction conditions: EDAMs 1 (1.1 mmol), BIDs 2 (1.0 mmol), and EtOH (20 mL).

Isolated yields based on BIDs 2.

To obtain the indenopyridine compound library, we further explored the universality of the cascade reaction for synthn class="Chemical">esis of compounds 4. A variety of EDAMs 1 and BIDs 2 were combined in this reaction under the optimal conditions (Table , entries 1–13). The results showed that the substituted EDAMs 1 had only a slight effect on the yields of compounds 4. In addition, the different substituents (H, F, Cl, Me, and OMe) at the 4 and 4′ positions of BIDs 2 also had a slight effect on the yield of compounds 4. In general, the yield of the electron-withdrawing-group-substituted BIDs 2 was higher than that of the electron-donating-group-substituted compound (Table , entry 1 vs 7–8 vs 9). In summary, all of EDAMs 1 and BIDs 2 can be used as substrates to produce high yields of the target compounds 4.

Table 3

Synthesis of Indenopyridine Compounds 4a

entry	R	R′	4	yield (%)b
1	p-FC6H4CH2	F	4a	90
2	p-FC6H4CH2	Me	4b	89
3	p-ClC6H4CH2	F	4c	85
4	p-ClC6H4CH2 CH2	H	4d	89
5	p-ClC6H4CH2	Me	4e	84
6	C6H5CH2	OMe	4f	89
7	C6H5CH2CH2	F	4g	88
8	C6H5CH2CH2	Cl	4h	88
9	C6H5CH2CH2	OMe	4i	83
10	p-OMeC6H4CH2CH2	F	4j	87
11	p-OMeC6H4CH2CH2	H	4k	86
12	p-OMeC6H4CH2CH2	Me	4l	89
13	p-OMeC6H4CH2CH2	OMe	4m	82

Reaction conditions: EDAMs 1 (1.1 mmol), BIDs 2 (1.0 mmol), and 1,4-dioxane (20 mL).

Isolated yields based on BIDs 2.

Products 3–4 were characterized by proton nuclear magnetic resonance (n class="Chemical">1H NMR), 13C nuclear magnetic resonance (13C NMR), Fourier transform infrared (FTIR) spectroscopy, and high-resolution mass spectrometry (HRMS). The results were all in agreement with the proposed structures. To further testify the structure of the highly functionalized indenopyridine derivatives, compound 4h was selected as the representative compound and characterized by X-ray crystallography, as shown in Scheme (CCDC 1885549) (ellipsoids are drawn at the 30% probability level).

Scheme 2

Mechanism for the Synthesis of Target Compounds 3–4

A proposed mechanism for this cascade reaction is shown in Scheme . First, the α-C of EDAMs 1 attacks the C=C bond of the BIDs 1 to generate the intermediatn class="Chemical">es 5 via a Michael reaction promoted by the base (EDAMs 1); high site-selectivity of this step is vital. Second, the intermediates 5 form the intermediates 6 via imine–enamine tautomerization. Next, the intermediates 7 are obtained through the enol–keto tautomerization of intermediate 6. Then, the intermediates 8 are produced by the intramolecular cyclization of the intermediates 7 where the amino group attacks the carbonyl of intermediates 7. Finally, the intermediate 8 loses one molecule of water to produce the target compounds 3.

The target compounds 3 can be easily oxidized by oxygen of air at high temperature (by refluxing n class="Chemical">1,4-dioxane). This oxidation reaction can also proceed at room temperature for 1–2 weeks. For example, when we cultivate the single crystal of compound 3m (for about 2 weeks), the only result is the structure of 4h rather than that of the compound 3m. We believe that the target compounds 3 produce compounds 4 via oxidation reactions.

Conclusions

We report a concise and environmentally friendly route for the synthesis of diverse n class="Chemical">IDDPs (3) via a cascade reaction of 1,1-eneamines (1) with benzylidene-1H-indene-1,3(2H)-diones (BIDs) (2) in ethanol media without any promoters. The targeted compounds were efficiently obtained by only filtration without any further post-treatment. Indenopyridine compounds (4) were constructed by the cascade reaction of EDAMs 1 with BIDs 2 in 1,4-dioxane and refluxing for 12 h without any promoters. The result was two kinds of indenopyridine derivatives 3–4 through alternative solvents and temperatures. The reaction had the following features: mild temperature, atom economy, high yields, and potential biological activity of the product.

Experimental Section

General Methods

All compounds were fully characterized by spectroscopic data. The NMR spectra were recorded on a Bruker DRX500 or DRX600. Chemical shifts (δ) are expressed in parts per million, J valun class="Chemical">es are given in hertz, and deuterated dimethyl sulfoxide (DMSO)-d6 or CDCl3 was used as a solvent. IR spectra were recorded on an FTIR Thermo Nicolet Avatar 360 using a KBr pellet. The reactions were monitored by thin-layer chromatography (TLC) using silica gel GF254. The melting points were determined on an XT-4A melting point apparatus and were uncorrected. HRMS were performed on an Agilent LC/MSD TOF instrument. X-ray diffraction was carried out by APEX DUO.

All chemicals and solvents were used as received without further purification unless otherwise stated. All chemicals were purchased from Adamas-β. Column chromatography was performed on n class="Chemical">silica gel (Qingdao, 200–300 mesh). Compounds 1 were prepared according to the literature.[50,51]

General Procedure for the Synthesis of Compounds 3a–u

EDAMs 1 (1.1 mmol) were dissolved in n class="Chemical">ethanol (20 mL), and then, BIDs 2 (1.0 mmol) were added to the mixture. The mixture was stirred by refluxing for about 6 h until full consumption of BIDs 2, which was observed by thin-layer chromatography (TLC). The formed precipitate was then filtered and washed with ethanol and a mixture of petroleum ether and ethyl acetate (petro/AcOEt = 1/1) solution to produce the pure products 3a–u. The products were further identified by NMR spectroscopy, FTIR spectroscopy, and HRMS.

2-((4-Fluorobenzyl)amino)-4-(4-fluorophenyl)-3-nitro-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3a)

Red solid; mp: 156.6–157.5 °C; IR (KBr): 3069, 1701, 1625, 1508, 1343, 1228 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 4.90–4.98 (m, n class="Chemical">1H, ArH), 5.02–5.09 (m, 2H, CH2), 7.08 (t, J = 8.8 Hz, 2H, ArH), 7.26–7.30 (m, 5H, ArH), 7.31–7.38 (m, 1H, ArH), 7.47–7.55 (m, 3H, ArH), 7.81 (d, J = 7.5 Hz, 1H, ArH), 10.27 (s, 1H, NH), 11.55–11.62 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.5, 45.4, 110.8, 112.4, 115.2 (d, J = 20.0 Hz), 116.2 (d, J = 21.0 Hz), 121.1, 121.7, 129.8, 130.2, 130.8, 132.7, 132.8, 133.5, 139.8, 151.7, 152.1, 161.4 (d, J = 240.0 Hz), 162.2 (d, J = 242.5 Hz), 190.8. HRMS (TOF ES+): m/z calcd for C25H18F2N3O3 [M + H]+, 446.1311; found, 446.1309.

4-(4-Chlorophenyl)-2-((4-fluorobenzyl)amino)-3-nitro-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3b)

Red solid; mp: 222.6–223.5 °C; IR (KBr): 3442, 1689, 1631, 1511, 1342, 1070 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 4.82–5.01 (m, n class="Chemical">3H, 1CH2, 1ArH), 7.17–7.38 (m, 8H, CH2), 7.47–7.55 (m, 3H, ArH), 7.78–7.87 (m, 1H, ArH), 10.28 (s, 1H, NH), 11.56–11.60 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.8, 45.4, 110.6, 112.0, 116.2 (d, J = 21.3 Hz), 121.1, 121.7, 128.5, 129.8, 130.1, 130.2, 130.3, 130.5, 130.9, 132.6, 132.9, 133.5, 142.6, 151.7, 152.2, 162.2 (d, J = 242.5 Hz), 190.7. HRMS (TOF ES+): m/z calcd for C25H18ClFN3O3 [M + H]+, 462.1015; found, 462.1014.

2-((4-Fluorobenzyl)amino)-3-nitro-4-(p-tolyl)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3c)

Red solid; mp: 187.8–188.7 °C; IR (KBr): 3442, 1688, 1631, 1511, 1342, 1069 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 2.22 (s, n class="Chemical">3H, CH3), 4.92–5.06 (m, 3H, 1CH2, 1ArH), 7.05 (d, J = 7.9 Hz, 2H, ArH), 7.13 (d, J = 8.0 Hz, 2H, ArH), 7.26–7.29 (m, 3H, ArH), 7.30–7.37 (m, 1H, ArH), 7.46–7.54 (m, 3H, ArH), 7.78 (d, J = 7.3 Hz, 1H, ArH), 10.23 (s, 1H, NH), 11.54–11.59 (m, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 21.0, 37.7, 45.3, 111.0, 112.9, 116.2 (d, J = 21.0 Hz), 120.9, 121.7, 127.8, 129.1, 130.2, 130.4, 130.7, 132.8, 133.6, 136.0, 136.4, 140.7, 151.7, 151.9, 162.2 (d, J = 241.5 Hz), 190.8. HRMS (TOF ES+): m/z calcd for C26H21FN3O3 [M + H]+, 442.1561; found, 442.1565.

2-((4-Chlorobenzyl)amino)-4-(4-chlorophenyl)-3-nitro-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3d)

Red solid; mp: 215.2–216.1 °C; IR (KBr): 3309, 1688, 1627, 1341, 1092, 1070 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 4.95–4.97 (m, n class="Chemical">1H, ArH), 5.04–5.10 (m, 2H, CH2), 7.29–7.37 (m, 6H, ArH), 7.47–7.53 (m, 5H, ArH), 7.78–7.82 (m, 1H, ArH), 10.27 (s, 1H, NH), 11.59 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.8 45.3, 110.6, 121.1, 121.8, 121.8, 128.5, 129.3, 129.3, 129.8, 129.8, 129.9, 129.9, 130.9, 131.5, 132.9, 136.4, 142.6, 151.8, 152.2, 190.7. HRMS (TOF ES+): m/z calcd for C25H17Cl2N3O3 [M + H]+, 478.0720; found, 478.0718.

2-((4-Chlorophenyl)amino)-3-nitro-4-phenyl-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3e)

Red solid; mp: 251.4–252.3 °C; IR (KBr): 3059, 1698, 1616, 1520, 1351, 1329 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 5.16 (s, n class="Chemical">1H, ArH), 7.15–7.21 (m, 1H, ArH), 7.25–7.30 (m, 6H, ArH), 7.32–7.44 (m, 1H, ArH), 7.48–7.58 (m, 1H, ArH), 7.59–7.64 (m, 2H, ArH), 7.72–7.80 (m, 2H, ArH), 10.73 (s, 1H, NH), 12.05 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 38.4, 112.5, 112.9, 121.1, 121.6, 125.0, 126.9, 127.1, 128.0, 128.3, 128.7, 128.9, 129.8, 130.7, 131.3, 132.7, 135.8, 136.4, 143.6, 190.8. HRMS (TOF ES+): m/z calcd for C24H17ClN3O3 [M + H]+, 430.0953; found, 430.0955.

4-(4-Methoxyphenyl)-3-nitro-2-(phenethylamino)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3f)

Red solid; mp: 220.7–221.6 °C; IR (KBr): 3443, 1699, 1633, 1510, 1324, 1071 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 3.03 (t, J = 7.0 Hz, 2H, CH2), 3.68 (s, n class="Chemical">1H, OCH3), 3.96–4,03 (m, 2H, NCH2), 4.93 (s, 1H, ArH), 6.78 (d, J = 8.5 Hz, 2H, ArH), 7.09 (d, J = 8.5 Hz, 2H, ArH), 7.20–7.29 (m, 2H, ArH), 7.32–7.37 (m, 5H, ArH), 7.46–7.50 (m, 1H, ArH), 7.82 (d, J = 7.5 Hz, 1H, ArH), 9.98 (s, 1H, NH), 11.36–11.43 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 35.3, 37.2, 44.1, 55.5, 110.7 112.7, 113.9, 121.1, 121.6, 127.1, 128.9, 129.0, 129.0, 129.4, 130.6, 132.7, 135.8, 136.5, 138.6, 151.7, 151.9, 158.3, 190.9. HRMS (TOF ES+): m/z calcd for C27H24N3O4 [M + H]+, 454.1761; found, 454.1761.

2-((4-Chlorobenzyl)amino)-3-nitro-4-(p-tolyl)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3g)

Red solid; mp: 206.5–207.4 °C; IR (KBr): 3438, 1701, 1631, 1520, 1331, 1320 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 2.22 (s, n class="Chemical">3H, CH3), 4.91–4.99 (m, 1H, ArH), 5.00 (s, 1H, CH2), 5.02–5.10 (m, 1H, CH2), 7.05 (d, J = 8.0 Hz, 2H, ArH), 7.12 (d, J = 7.5 Hz, 2H, ArH), 7.26–7.31 (m, 1H, ArH), 7.31–7.38 (m, 1H, ArH), 7.47–7.52 (m, 5H, ArH), 7.76 (d, J = 7.0 Hz, 1H, ArH), 10.22 (s, 1H, NH), 11.53–11.60 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 21.1, 37.7, 45.3, 111.0, 112.9, 120.9, 121.7, 127.8, 129.1, 129.3, 130.1, 130.7, 132.7, 132.8, 132.9, 136.0, 136.4, 136.5, 140.7, 151.8, 151.9, 190.8. HRMS (TOF ES+): m/z calcd for C26H21ClN3O3 [M + H]+, 458.1266; found, 458.1264.

2-((4-Chlorophenyl)amino)-4-(4-methoxyphenyl)-3-nitro-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3h)

Red solid; mp: 229.2–230.1 °C; IR (KBr): 3060, 1699, 1617, 1510, 1351, 1258 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 3.70–3.77 (m, n class="Chemical">3H, OCH3), 5.10 (s, 1H, ArH), 6.85 (d, J = 8.4 Hz, 2H, ArH), 7.22 (d, J = 8.4 Hz, 2H, ArH), 7.28–7.37 (m, 2H, ArH), 7.38–7.45 (m, 1H, ArH), 7.49–7.62 (m, 1H, ArH), 10.69 (s, 1H, NH), 12.02 (s, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 37.4, 55.5, 112.8, 113.2, 114.1, 114.1, 121.0, 121.5, 126.8, 129.0, 129.0, 130.0, 130.6, 131.2, 132.7, 132.9, 135.7, 136.5, 149.3, 158.5, 190.9. HRMS (TOF ES+): m/z calcd for C25H19ClN3O4 [M + H]+, 460.1059; found, 460.1061.

2-((4-Chlorophenethyl)amino)-4-(4-methoxyphenyl)-3-nitro-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3i)

Red solid; mp: 233.0–233.9 °C; IR (KBr): 3229, 1693, 1633, 1508, 1313, 1268 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 3.04 (t, J = 7.0 Hz, 2H, CH2), 3.68 (s, n class="Chemical">3H, OCH3), 3.96–4.03 (m, 2H, NCH2), 6.79 (d, J = 8.5 Hz, 2H, ArH), 7.09 (d, J = 8.5 Hz, 2H, ArH), 7.24–7.30 (m, 1H, ArH), 7.30–7. 37 (m, 1H, ArH), 7.38 (s, 4H, ArH), 7.44–7.51 (m, 1H, ArH), 7.81 (d, J = 7.5 Hz, 1H, ArH), 9.97 (s, 1H, NH), 11.36–11.42 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 34.6, 37.1, 43.8, 55.5, 110.7, 112.7, 113.9, 121.1, 121.5, 128.7, 128.9, 130.6, 131.3, 131.8, 132.7, 132.8, 135.8, 136.5, 137.7, 151.8, 151.9, 158.3, 190.8. HRMS (TOF ES+): m/z calcd for C27H23ClN3O4 [M + H]+, 488.1372; found, 488.1373.

4-(4-Fluorophenyl)-3-nitro-2-(phenethylamino)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3j)

Red solid; mp: 209.2–210.1 °C; IR (KBr): 3436, 1697, 1632, 1505, 1356, 1068 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 3.04 (t, J = 7.1 Hz, 2H, CH2), 3.97–4.03 (m, 2H, NCH2), 4.98 (s, n class="Chemical">1H, ArH), 7.02–7.08 (m, 2H, ArH), 7.21–7.24 (m, 3H, ArH), 7.25–7.30 (m, 1H, ArH), 7.32–7.37 (m, 5H, ArH), 7.45–7.51 (m, 1H, ArH), 7.84 (d, J = 7.2 Hz, 1H, ArH), 10.01 (s, 1H, NH), 11.39–11.43 (m, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 35.3, 37.5, 44.1, 110.3, 112.1, 115.2 (d, J = 21.0 Hz), 121.3, 121.6, 127.1, 129.0, 129.4, 129.7, 129.8, 130.7, 132.7, 136.4, 138.6, 139.9, 151.8, 152.2, 161.3 (d, J = 240.0 Hz), 190.8. HRMS (TOF ES+): m/z calcd for C26H21FN3O3 [M + H]+, 442.1561; found, 442.1563.

4-(4-Methoxyphenyl)-3-nitro-2-(phenylamino)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3k)

Red solid; mp: 226.5–227.4 °C; IR (KBr): 3048, 2928, 1698, 1657, 1619, 1512 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 3.70 (s, n class="Chemical">3H, OCH3), 5.10 (s, 1H, ArH), 6.85 (d, J = 8.5 Hz, 2H, ArH), 7.22 (d, J = 8.5 Hz, 2H, ArH), 7.28–7.43 (m, 3H, ArH), 7.46–7.50 (m, 1H, ArH), 7.51–7.59 (m, 5H, ArH), 10.80 (s, 1H, NH), 12.18 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.4, 55.5, 112.8, 113.0, 114.1, 121.0, 121.5, 124.7, 127.0, 129.0, 130.2, 130.6, 132.7, 132.9, 135.7, 136.5, 136.6, 149.3, 152.2, 158.5, 190.9. HRMS (TOF ES+): m/z calcd for C25H20N3O4 [M + H]+, 426.1448; found, 426.1451.

2-(Benzylamino)-4-(4-chlorophenyl)-3-nitro-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3l)

Red solid; mp: 230.2–231.1 °C; IR (KBr): 3442, 1689, 1631, 1511, 1342, 1070 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 4.92–5.00 (m, n class="Chemical">1H, ArH), 5.03–5.09 (m, 2H, CH2), 7.27–7.39 (m, 7H, ArH), 7.43–7.52 (m, 5H, ArH), 7.82 (d, J = 7.0 Hz, 1H, ArH), 10.31 (s, 1H, NH), 11.60–11.66 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.8, 46.1, 110.5, 112.0, 121.2, 121.7, 128.0, 128.4, 128.5, 128.8, 129.8, 130.9, 131.5, 132.6, 132.9, 136.3, 137.3, 142.6, 151.8, 152.3, 190.8. HRMS (TOF ES+): m/z calcd for C25H19ClN3O3 [M + H]+, 444.1109; found, 444.1114.

4-(4-Chlorophenyl)-3-nitro-2-(phenethylamino)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3m)

Red solid; mp: 164.9–165.8 °C; IR (KBr): 3442, 1630, 1513, 1347, 1087, 1068 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 3.01–3.08 (m, 2H, CH2), 3.98–4.03 (m, 2H, NCH2), 4.97 (s, n class="Chemical">1H, ArH), 7.21–7.38 (m, 12H, ArH), 7.44–7.51 (m, 1H, ArH), 7.85 (d, J = 7.0 Hz, 1H, ArH), 10.01 (s, 1H, NH), 11.42 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 35.2, 37.8, 44.1, 110.1, 111.8, 121.3, 121.6, 127.1, 128.4, 129.0, 129.4, 129.4, 129.8, 130.8, 131.4, 132.7, 136.3, 138.6, 142.7, 151.8, 152.3, 190.7. HRMS (TOF ES+): m/z calcd for C26H21ClN3O3 [M + H]+, 458.1266; found, 458.1268.

3-Nitro-2-(phenethylamino)-4-phenyl-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3n)

Red solid; mp: 223.5–224.4 °C; IR (KBr): 3442, 1702, 1630, 1519, 1314, 1070 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 3.02–3.08 (m, 2H, CH2), 3.98–4.03 (m, 2H, NCH2), 4.98 (s, n class="Chemical">1H, ArH), 7.13–7.49 (m, 13H, ArH), 7.80–7.86 (m, 1H, ArH), 10.00 (s, 1H, NH), 11.40–11.45 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 35.3, 38.1, 44.1, 110.4 112.4, 121.2 121.6, 126.9, 127.1, 127.9, 128.5, 129.0, 129.4, 130.7, 132.7, 132.7, 136.4, 138.6, 143.7, 151.8, 152.2, 190.8. HRMS (TOF ES+): m/z calcd for C26H21N3O3 [M + H]+, 424.1656; found, 424.1656.

2-(Benzylamino)-3-nitro-4-(p-tolyl)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3o)

Red solid; mp: 234.1–235.0 °C; IR (KBr): 3441, 1670, 1631, 1359, 1158, 1065 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 2.22 (s, n class="Chemical">3H, CH3), 4.98–5.05 (m, 3H, 1CH2, 1ArH), 7.05 (d, J = 7.9 Hz, 2H, ArH), 7.14 (d, J = 8.0 Hz, 2H, ArH), 7.21–7.26 (m, 1H, ArH), 7.27–7.30 (m, 1H, ArH), 7.32–7.36 (m, 2H, ArH), 7.42–7.48 (m, 4H, ArH), 7.79 (d, J = 7.2 Hz, 1H, ArH), 10.24 (s, 1H, NH), 11.58–11.65 (m, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 21.0, 37.7, 46.1, 111.0 112.9, 120.9, 121.7, 127.8, 128.0, 128.2, 128.3, 129.1, 129.4, 130.7, 132.8, 136.0, 136.4, 137.3, 140.7, 151.8, 151.9, 190.8. HRMS (TOF ES+): m/z calcd for C26H22N3O3 [M + H]+, 424.1656; found, 424.1657.

4-(4-Methoxyphenyl)-3-nitro-2-(phenylamino)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3p)

Red solid; mp: 226.5–227.4 °C; IR (KBr): 3048, 2928, 1698, 1657, 1619, 1512 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 3.70 (s, n class="Chemical">3H, OCH3), 5.10 (s, 1H, ArH), 6.85 (d, J = 8.5 Hz, 2H, ArH), 7.22 (d, J = 8.5 Hz, 2H, ArH), 7.28–7.43 (m, 3H, ArH), 7.46–7.50 (m, 1H, ArH), 7.51–7.59 (m, 5H, ArH), 10.80 (s, 1H, NH), 12.18 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 37.4, 55.5, 112.8, 113.0, 114.1, 121.0, 121.5, 124.7, 127.0, 129.0, 130.2, 130.6, 132.7, 132.9, 135.7, 136.5, 136.6, 149.3, 152.2, 158.5, 190.9. HRMS (TOF ES+): m/z calcd for C25H20N3O4 [M + H]+, 426.1448; found, 426.1451.

4-(4-Methoxyphenyl)-3-nitro-2-(phenethylamino)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3q)

Red solid; mp: 220.7–221.6 °C; IR (KBr): 3443, 1699, 1633, 1510, 1324, 1071 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 3.03 (t, J = 7.0 Hz, 2H, CH2), 3.68 (s, n class="Chemical">1H, OCH3), 3.96–4,03 (m, 2H, NCH2), 4.93 (s, 1H, ArH), 6.78 (d, J = 8.5 Hz, 2H, ArH), 7.09 (d, J = 8.5 Hz, 2H, ArH), 7.20–7.29 (m, 2H, ArH), 7.32–7.37 (m, 5H, ArH), 7.46–7.50 (m, 1H, ArH), 7.82 (d, J = 7.5 Hz, 1H, ArH), 9.98 (s, 1H, NH), 11.36–11.43 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 35.3, 37.2, 44.1, 55.5, 110.7 112.7, 113.9, 121.1, 121.6, 127.1, 128.9, 129.0, 129.0, 129.4, 130.6, 132.7, 135.8, 136.5, 138.6, 151.7, 151.9, 158.3, 190.9. HRMS (TOF ES+): m/z calcd for C27H24N3O4 [M + H]+, 454.1761; found, 454.1761.

4-(4-Fluorophenyl)-2-((4-methoxyphenethyl)amino)-3-nitro-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3r)

Red solid; mp: 173.7–174.6 °C; IR (KBr): 3453, 1630, 1512, 1353, 1247, 1070 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 2.93–2.99 (m, 2H, CH2), 3.66 (s, n class="Chemical">3H, OCH3), 3.93–4.01 (m, 2H, NCH2), 4.98 (s, 1H, ArH), 6.86–6.89 (m, 2H, ArH), 7.03–7.06 (m, 2H, ArH), 7.21–7.28 (m, 5H, ArH), 7.30–7.37 (m, 1H, ArH), 7.45–7.50 (m, 1H, ArH), 7.82 (d, J = 7.3 Hz, 1H, ArH), 9.98 (s, 1H, NH), 11.35–11.41 (m, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 34.5, 37.5, 44.3, 55.4, 110.3, 112.1, 114.5, 115.2 (d, J = 21.0 Hz), 121.3, 121.6, 129.7, 129.7, 130.4, 130.4, 130.7, 132.7, 136.4, 139.9, 151.8, 152.2, 158.5, 161.3 (d, J = 240.0 Hz), 190.8. HRMS (TOF ES+): m/z calcd for C27H23FN3O4 [M + H]+, 472.1667; found, 472.1667.

4-(4-Chlorophenyl)-2-((4-methoxyphenethyl)amino)-3-nitro-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3s)

Red solid; mp: 213.2–214.1 °C; IR (KBr): 3394, 1702, 1656, 1616, 1593, 1339 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 2.96 (t, J = 7.0 Hz, 2H, CH2), 3.66 (s, n class="Chemical">1H, OCH3), 3.94–4.01 (m, 2H, NCH2), 4.97 (s, 1H, ArH), 6.88 (d, J = 8.5 Hz, 2H, ArH), 7.21 (d, J = 8.5 Hz, 2H, ArH), 7.23–7.31 (m, 5H, ArH), 7.32–7.39 (m, 1H, ArH), 7.46–7.53 (m, 1H, ArH), 7.84 (d, J = 7.5 Hz, 1H, ArH), 10.00 (s, 1H, NH), 11.36–11.42 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 34.5, 37.7, 44.4, 55.4, 110.1, 111.7, 114.4, 121.4, 121.6, 128.4, 129.8, 130.4, 130.5, 130.5, 130.8, 131.4, 132.7, 136.3, 142.7, 151.8, 152.4, 158.5, 190.8. HRMS (TOF ES+): m/z calcd for C27H23ClN3O4 [M + H]+, 488.1372; found, 488.1371.

2-((4-Methoxyphenethyl)amino)-3-nitro-4-phenyl-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3t)

Red solid; mp: 164.0–164.9 °C; IR (KBr): 3062, 1702, 1625, 1492, 1349,1267 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 2.94–3.00 (m, 2H, CH2), 3.67 (s, n class="Chemical">3H, OCH3), 3.94–4.01 (m, 2H, NCH2), 4.99 (s, 1H, ArH), 6.88 (d, J = 8.5 Hz, 2H, ArH), 7.11–7.18 (m, 1H, ArH), 7.19–7.28 (m, 7H, ArH), 7.31–7.38 (m, 1H, ArH), 7.45–7.52 (m, 1H, ArH), 7.82 (d, J = 7.0 Hz, 1H, ArH), 9.98 (s, 1H, NH), 11.37–11.43 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 34.5, 38.1, 44.3, 55.4, 110.4, 112.3, 114.4, 121.2, 121.6, 126.9, 127.9, 128.5, 130.4, 130.4, 130.7, 132.7, 136.4, 143.7, 151.9, 152.2, 158.5, 190.8. HRMS (TOF ES+): m/z calcd for C27H24N3O4 [M + H]+, 454.1761; found, 454.1758.

2-((4-Methoxyphenethyl)amino)-3-nitro-4-(p-tolyl)-1,4-dihydro-9H-indeno[2,1-b]pyridin-9-one (3u)

Red solid; mp: 217.2–218.1 °C; IR (KBr): 3455, 1640, 1512, 1342, 1247, 1070 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 2.19–2.29 (m, n class="Chemical">3H, CH3), 2.93–2.99 (m, 2H, CH2), 3.64–3.73 (m, 3H, OCH3), 3.93–3.99 (m, 2H, NCH2), 4.94 (s, 1H, ArH), 6.84–6.92 (m, 2H, ArH), 6.99–7.08 (m, 4H, ArH), 7.25–7.34 (m, 4H, ArH), 7.43–7.50 (m, 1H, ArH), 7.80 (d, J = 7.5 Hz, 1H, ArH), 9.93 (s, 1H, NH), 11.39 (d, J = 5.5 Hz, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 21.0, 34.5, 37.6, 44.3, 55.4, 110.5, 112.5, 114.4, 121.1, 121.5, 127.8, 129.1, 130.4, 132.6, 132.6, 132.6, 132.8, 135.9, 136.4, 140.8, 151.8, 152.0, 158.5, 190.8. HRMS (TOF ES+): m/z calcd for C28H26N3O4 [M + H]+, 468.1918; found, 468.1919.

General Procedure for the Synthesis of Compounds 4a–m

EDAMs 1 (1.1 mmol) were dissolved in n class="Chemical">1,4-dioxane (20 mL), and then, BIDs 2 (1.0 mmol) were added to the mixture. The mixture was stirred by refluxing for about 12 h until full consumption of BIDs 2, which was observed by thin-layer chromatography (TLC). The reaction solution was poured into 30 mL of water and extracted with an appropriate amount of ethyl acetate. The combined organic phases were dried with anhydrous Na2SO4 and then separated by column chromatography (petro/AcOEt = 30/1) to obtain pure target products 4a–m with 82–90% yield. The products were further identified by NMR spectroscopy, FTIR spectroscopy, and HRMS.

2-((4-Fluorobenzyl)amino)-4-(4-fluorophenyl)-3-nitro-9H-indeno[2,1-b]pyridin-9-one (4a)

Yellow solid; mp: 193.3–194.2 °C; IR (KBr): 3409, 1713, 1571, 1508, 1267, 1222 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 4.78–4.83 (m, 2H, CH2), 7.18 (t, J = 7.4 Hz, 2H, n class="Gene">ArH), 7.24–7.31 (m, 2H, ArH), 7.38–7.41 (m, 2H, ArH), 7.53–7.59 (m, 4H, ArH), 7.69–7.73 (m, 1H, ArH), 7.81–7.86 (m, 1H, ArH), 8.86–8.92 (m, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 44.5, 113.9, 115.5 (d, J = 21.0 Hz), 115.5 (d, J = 21.0 Hz), 121.6, 123.4, 128.0, 130.5, 130.6, 130.8, 132.9, 135.2, 135.7, 137.2, 140.5, 143.1, 153.6, 161.8 (d, J = 241.5 Hz), 163.0 (d, J = 243.0 Hz), 167.3, 188.1. HRMS (TOF ES+): m/z calcd for C25H16F2N3O3 [M + H]+, 444.1154; found, 444.1158.

2-((4-Fluorobenzyl)amino)-3-nitro-4-(p-tolyl)-9H-indeno[2,1-b]pyridin-9-one (4b)

Yellow solid; mp: 203.4–204.3 °C; IR (KBr): 3444, 2924, 1707, 1587, 1522, 1273 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 2.38 (s, n class="Chemical">3H, CH3), 4.79 (d, J = 6.0 Hz, 2H, CH2), 7.16–7.25 (m, 6H, ArH), 7.52–7.57 (m, 4H, ArH), 7.67–7.70 (m, 1H, ArH), 7.82 (d, J = 7.5 Hz, 1H, ArH), 8.76–8.79 (m, 1H, 1NH); 13C NMR (125 MHz, DMSO-d6): δ = 21.4, 44.5, 113.7, 115.5 (d, J = 21.3 Hz), 121.5, 123.3, 128.2, 128.5, 129.1, 130.5, 131.2, 132.7, 135.1, 135.8, 137.1, 139.1, 140.5, 143.8, 153.4, 161.8 (d, J = 241.3 Hz), 167.22, 188.1. HRMS (TOF ES+): m/z calcd for C26H19FN3O3 [M + H]+, 440.1405; found, 440.1406.

2-((4-Chlorobenzyl)amino)-4-(4-fluorophenyl)-3-nitro-9H-indeno[2,1-b]pyridin-9-one (4c)

Yellow solid; mp: 191.6–192.5 °C; IR (KBr): 3402, 1710, 1571, 1531, 1520, 1269 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 4.81 (d, J = 5.5 Hz, 2H, CH2), 7.26–7.30 (m, 2H, n class="Gene">ArH), 7.38–7.42 (m, 4H, ArH), 7.51–7.59 (m, 4H, ArH), 7.68–7.72 (m, 1H, ArH), 7.81 (d, J = 7.0 Hz, 1H, ArH), 8.90–8.92 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 44.6, 114.0, 115.5 (d, J = 21.3 Hz), 121.6, 123.4, 128.0, 128.7, 130.3, 130.6, 130.8, 132.1, 134.2, 132.9, 135.2, 137.1, 138.6, 140.4, 143.1, 153.6, 163.0 (d, J = 243.8 Hz), 167.3, 188.1. HRMS (TOF ES+): m/z calcd for C25H16ClFN3O3 [M + H]+, 460.0859; found, 460.0861.

2-((4-Chlorophenethyl)amino)-3-nitro-4-phenyl-9H-indeno[2,1-b]pyridin-9-one (4d)

Yellow solid; mp: 253.0–253.9 °C; IR (KBr): 3379, 1705, 1611, 1589, 1522, 1276 cm–1; 1H NMR (500 MHz, DMSO-d6 + n class="Chemical">CDCl3): δ = 2.98–3.01 (m, 2H, CH2), 3.86–3.90 (m, 2H, NCH2), 7.30–7.32 (m, 6H, ArH), 7.43–7.45 (m, 3H, ArH), 7.54–7.56 (m, 2H, ArH), 7.67–7.70 (m, 1H, NH), 7.82 (d, J = 7.0 Hz, 1H, ArH), 8.27–8.29 (m, 1H, ArH); 13C NMR (125 MHz, DMSO-d6 + CDCl3): δ = 34.8, 43.3, 113.4, 121.4, 123.1, 128.0, 128.3, 128.7, 129.2, 130.7, 130.9, 131.5, 131.9, 132.5, 134.8, 137.2, 138.5, 140.6, 144.0, 153.9, 167.5, 188.0. HRMS (TOF ES+): m/z calcd for C26H19ClN3O3 [M + H]+, 456.1109; found, 456.1106.

2-((4-Chlorobenzyl)amino)-3-nitro-4-(p-tolyl)-9H-indeno[2,1-b]pyridin-9-one (4e)

Yellow solid; mp: 202.9–203.8 °C; IR (KBr): 3414, 1708, 1617, 1589, 1271, 624 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 2.38, (s, n class="Chemical">3H, CH3),4.79 (d, J = 5.2 Hz, 2H, CH2), 7.20–7.25 (m, 4H, ArH), 7.41 (d, J = 8.2 Hz, 2H, ArH), 7.50–7.57 (m, 4H, ArH), 7.67–7.69 (m, 1H, ArH), 7.79 (d, J = 7.4 Hz, 1H, ArH), 8.77–8.79 (m, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 21.4, 44.6, 113.8, 121.5, 123.3, 128.2, 128.5, 128.7, 129.1, 130.3, 131.3, 132.0, 132.7, 135.1, 137.0, 138.7, 139.1, 140.5, 143.9, 153.4, 167.2, 188.1. HRMS (TOF ES+): m/z calcd for C26H19ClN3O3 [M + H]+, 456.1109; found, 456.1114.

2-(Benzylamino)-4-(4-methoxyphenyl)-3-nitro-9H-indeno[2,1-b]pyridin-9-one (4f)

Yellow solid; mp: 227.2–228.1 °C; IR (KBr): 3408, 1706, 1584, 1521, 1507, 1276 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 3.83 (s, n class="Chemical">3H, OCH2), 4.79–4.84 (m, 2H, CH2), 6.96–7.02 (m, 2H, ArH), 7.21–7.30 (m, 3H, ArH), 7.32–7.38 (m, 2H, ArH), 7.46–7.51 (m, 2H, ArH), 7.50–7.57 (m, 2H, ArH), 7.63–7.69 (m, 1H, ArH), 7.74–7.79 (m, 1H, ArH), 8.71–8.76 (m, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 45.1, 55.7, 113.6, 114.0, 121.4, 123.2, 123.3, 127.4, 128.4, 128.8, 129.9, 131.3, 132.6, 135.0, 137.1, 139.7, 140.5, 143.5, 153.4, 160.5, 167.2, 188.2. HRMS (TOF ES+): m/z calcd for C26H20N3O4 [M + H]+, 438.1448; found, 438.1452.

4-(4-Fluorophenyl)-3-nitro-2-(phenethylamino)-9H-indeno[2,1-b]pyridin-9-one (4g)

Yellow solid; mp: 208.7–209.6 °C; IR (KBr): 3364, 1714, 1608, 1536, 1502, 1271 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 2.98 (t, J = 7.6 Hz, 2H, CH2), 3.85–3.88 (m, 2H, NCH2), 7.22–7.24 (m, n class="Chemical">1H, ArH), 7.26–7.29 (m, 2H, ArH), 7.33–7.34 (m, 4H, ArH), 7.35–7.39 (m, 3H, ArH), 7.53–7.58 (m, 2H, ArH), 7.69–7.72 (m, 1H, ArH), 7.82 (d, J = 7.3 Hz, 1H, ArH), 8.40–8.42 (m, 1H, 1NH); 13C NMR (150 MHz, DMSO-d6): δ = 35.4, 43.6, 113.5, 115.5 (d, J = 21.0 Hz), 121.5, 123.3, 126.7, 128.2, 128.9, 129.2, 130.5, 130.5, 132.8, 135.1, 137.2, 139.6, 140.5, 143.3, 153.9, 162.9 (d, J = 244.5 Hz), 167.5, 188.0. HRMS (TOF ES+): m/z calcd for C26H19FN3O3 [M + H]+, 440.1405; found, 440.1407.

4-(4-Chlorophenyl)-3-nitro-2-(phenethylamino)-9H-indeno[2,1-b]pyridin-9-one (4h)

Yellow solid; mp: 206.2–207.1 °C; IR (KBr): 3414, 1712, 1575, 1521, 1270, 77 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 2.97–3.00 (m, 2H, CH2), 3.86–3.90 (m, 2H, CH2), 7.21–7.24 (m, n class="Chemical">1H, ArH), 7.33–7.36 (m, 6H, ArH), 7.50–7.60 (m, 4H, ArH), 7.73 (t, J = 6.8 Hz, 1H, ArH), 7.85 (d, J = 7.5 Hz, 1H, ArH), 8.47–8.49 (m, 1H, 1NH); 13C NMR (125 MHz, DMSO-d6): δ = 35.4, 43.7, 113.5, 121.6, 123.4, 126.7, 128.6, 128.9, 129.3, 130.1, 131.0, 132.9, 134.2, 135.2, 137.3, 139.6, 140.5, 143.2, 154.1, 167.5, 188.0. HRMS (TOF ES+): m/z calcd for C26H19ClN3O3 [M + H]+, 456.1109; found, 456.1111.

4-(4-Methoxyphenyl)-3-nitro-2-(phenethylamino)-9H-indeno[2,1-b]pyridin-9-one (4i)

Yellow solid; mp: 182.7–183.6 °C; IR (KBr): 3393, 1707, 1582, 1508, 1257, 1178 cm–1; 1H NMR (500 MHz, DMSO-d6): δ = 2.97 (t, J = 7.5 Hz, 2H, CH2), 3.83–3.87 (m, 5H, NCH2, OCH3), 6.99 (d, J = 8.5 Hz, 2H, n class="Gene">ArH), 7.21–7.27 (m, 3H, ArH), 7.32–7.35 (m, 4H, ArH), 7.53–7.57 (m, 2H, ArH), 7.68–7.71 (m, 1H, ArH), 7.81 (d, J = 7.0 Hz, 1H, ArH), 8.23–8.25 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6): δ = 35.4, 43.6, 55.7, 113.3, 114.0, 121.4, 123.2, 123.5, 126.7, 128.9, 129.2, 129.9, 131.1, 132.6, 135.0, 137.2, 139.7, 140.6, 143.7, 153.7, 160.4, 167.4, 188.2. HRMS (TOF ES+): m/z calcd for C27H22N3O4 [M + H]+, 452.1605; found, 452.1607.

4-(4-Fluorophenyl)-2-((4-methoxyphenethyl)amino)-3-nitro-9H-indeno[2,1-b]pyridin-9-one (4j)

Yellow solid; mp: 229.1–231.0 °C; IR (KBr): 3369, 2941, 1716, 1581, 1536, 1272 cm–1; 1H NMR (500 MHz, DMSO-d6 + n class="Chemical">CDCl3): δ = 2.92–2.95 (m, 2H, CH2), 3.32 (s, 1H, OCH3), 3.86–3.87 (m, 2H, CH2), 6.85–6.87 (m, 2H, ArH), 7.20–7.24 (m, 4H, ArH), 7.32–7.36 (m, 2H, ArH), 7.52–7.57 (m, 2H, ArH), 7.68–7.72 (m, 1H, ArH), 7.82–7.86 (m, 2H, ArH), 8.30–8.34 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + CDCl3): δ = 34.6, 43.8, 55.3, 113.5, 114.2, 115.3 (d, J = 21.3 Hz), 121.5, 123.1, 128.2, 130.1, 130.2, 131.3, 132.5, 134.8, 137.3, 140.6, 143.3, 154.1, 158.2, 162.9 (d, J = 245.0 Hz), 167.5, 188.0. HRMS (TOF ES+): m/z calcd for C27H21FN3O4 [M + H]+, 470.1511; found, 470.1513.

2-((4-Methoxyphenethyl)amino)-3-nitro-4-phenyl-9H-indeno[2,1-b]pyridin-9-one (4k)

Yellow solid; mp: 185.0–186.0 °C; IR (KBr): 3415, 1716, 1637, 1617, 1582, 1272 cm–1; 1H NMR (600 MHz, DMSO-d6): δ = 2.91 (t, J = 7.5 Hz, 2H, CH2), δ = 3.70 (s, n class="Chemical">3H, OCH3), 3.80–3.83 (m, 2H, CH2), 6.88 (d, J = 8.5 Hz, 2H, ArH), 7.23 (d, J = 8.5 Hz, 2H, ArH), 7.30–7.31 (m, 2H, ArH), 7.42–7.47 (m, 3H, ArH), 7.52–7.57 (m, 2H, ArH); 7.68–7.70 (m, 1H, ArH), 7.80 (d, J = 7.4 Hz, 1H, ArH), 8.30–8.32 (m, 1H, NH); 13C NMR (150 MHz, DMSO-d6): δ = 34.6, 43.8, 55.5, 113.3, 114.4, 121.5, 123.2, 128.1, 128.4, 129.4, 130.2, 130.6, 131.5, 131.9, 132.7, 135.0, 137.2, 140.5, 144.0, 153.9, 158.3, 167.4, 188.0. HRMS (TOF ES+): m/z calcd for C27H22N3O4 [M + H]+, 452.1605; found, 452.1605.

2-((4-Methoxyphenethyl)amino)-3-nitro-4-(p-tolyl)-9H-indeno[2,1-b]pyridin-9-one (4l)

Yellow solid; mp: 200.2–201.0 °C; IR (KBr): 3418, 2933, 1715, 1580, 1509, 1272 cm–1; 1H NMR (500 MHz, DMSO-d6 + n class="Chemical">CDCl3): δ = 2.40 (s, 3H, CH3), 2.92 (t, J = 7.3 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 3.83–3.86 (m, 2H, NCH2), 6.86 (d, J = 8.0 Hz, 2H, ArH), 7.18–7.24 (m, 6H, ArH), 7.52–7.53 (m, 2H, ArH), 7.66–7.68 (m, 1H, ArH), 7.82 (d, J = 7.0 Hz, 1H, ArH), 8.18 (m, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + CDCl3): δ = 21.4, 34.6, 43.8, 55.3, 113.3, 114.2, 121.3, 123.0, 128.0, 128.9, 128.9, 130.1, 130.8, 131.4, 132.3, 134.7, 137.3, 138.8, 140.7, 144.1, 153.9, 158.2, 167.5, 188.0. HRMS (TOF ES+): m/z calcd for C28H24N3O4 [M + H]+, 466.1761; found, 466.1761.

2-((4-Methoxyphenethyl)amino)-4-(4-methoxyphenyl)-3-nitro-9H-indeno[2,1-b]pyridin-9-one (4m)

Yellow solid; mp: 217.5–218.4 °C; IR (KBr): 3418, 1709, 1586, 1510, 1467, 1247 cm–1; 1H NMR (500 MHz, DMSO-d6 + n class="Chemical">CDCl3): δ = 2.87–2.94 (m, 2H, CH2), 3.71 (s, 3H, OCH3), 3.78–3.85 (m, 5H, 1CH2, 1OCH3), 6.89 (d, J = 8.5 Hz, 2H, ArH), 7.00 (d, J = 8.7 Hz, 2H, ArH), 7.21–7.29 (m, 4H, ArH), 7.55–7.60 (m, 2H, ArH), 7.71–7.74 (m, 1H, NH), 7.81–7.86 (m, 1H, ArH), 8.18–8.24 (m, 1H, ArH); 13C NMR (125 MHz, DMSO-d6 + CDCl3): δ = 34.7, 43.8, 55.3, 55.5, 113.3, 113.8, 114.2, 121.3, 123.0, 123.6, 129.7, 130.1, 130.9, 131.4, 132.3, 134.6, 137.3, 140.7, 143.9, 153.9, 158.2, 160.4, 167.5, 188.1. HRMS (TOF ES+): m/z calcd for C28H24N3O5 [M + H]+, 482.1710; found, 482.1710.