Three-component site-selective synthesis of highly substituted 5H

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Three-component site-selective synthesis of highly substituted 5H-chromeno-[4,3-b]pyridines Cong-Hai Zhang, Rong Huang, Xing-Mei Hu, Jun Lin, and Sheng-Jiao Yan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00099 • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 12, 2018

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The Journal of Organic Chemistry

Three-component site-selective synthesis of highly substituted 5H-chromeno-[4,3-b]pyridines Cong-Hai Zhang, Rong Huang, Xing-Mei Hu, Jun Lin* and Sheng-Jiao Yan* Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China. KEYWORDS:

Three-component,

Site-selective,

5-H-Chromeno[4,3-b]pyridines,

3-

Formylchromones, 1,1-Enediamines.

ACS Paragon Plus Environment

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ABSTRACT: An efficient and concise one-pot procedure was developed based on a cascade reaction of 3-formylchromones 1 and different types of 1,1-enediamines (EDAMs) 2 with different alcohols or amines 3 by a site-selective synthesis of 5H-chromeno[4,3-b]pyridines in an environmentally friendly solvent. This protocol is especially suitable for the efficient and rapid parallel synthesis of 5H-chromeno[4,3-b]pyridine compounds. It also has some advantages, such as convenience of operation, short reaction times, use of green solvent and ease of purification by washing the crude products with ethanol.


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INTRODUCTION With the development of green chemistry, environmentally friendly and sustainable synthetic

methods and technologies have been widely adopted for chemical synthesis of compounds.1-2 Among them, group-assisted purification (GAP)3 chemistry, which does not involve the use of traditional purification by chromatography or recrystallization, is a conception that encourages researchers to do their best to search for environmentally benign reagents and reactions to reduce the waste generated from silica and solvents, particularly toxic solvents. In addition, compared to the traditional stepwise reaction process, multicomponent reactions (MCRs)4-5 are also valuable for environmentally-friendly chemistry due to their simple operation, short reaction time, reduced use of toxic and hazardous chemicals, lower production of chemical by-products, ease of processing for isolation and purification, high yield, saving of materials. MCRs can be largely responsible for increasing the rate of utilization of atomic reactions and usually can be used to make the natural products or complex biological molecules, which can solve complex problems in a simple synthetic way. 3-Formylchromones are a type of simple building blocks6-7 that usually act as the α,βunsaturated aldehydes that use C1 as 1,4-Michael acceptor and C4 as 1,2-addition acceptor to react with many kinds of bis-nucleophilic reagents for the synthesis of fused-ring compounds. However, the three reaction sites (C1, C3, C4) of 3-formylchromones (Scheme 1) are combined in one reaction to synthesize more complex compounds never reported before. Enamines including enaminones, enamine esters, heterocyclic ketene aminals (HKAs) and 1,1-enediamines (EDAMs) are fascinating and versatile building blocks which are widely used to synthesize various fused heterocyclic compounds.8-11 Some of these compounds have a wide range of biological activities.12-14


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HO O

O

Me N

O N

N

N

A cytotoxicity against cancer

O B tumor growth and metastasis inhibitory

O

O O D human dopamine D4 C antibacterial and receptor antagonist antimicrobial activities

HO

NO2

N R

O O

O

NHR' N

O

O

O

schumanniophytine: nervous system depressant

O

ZR''

Z=O, NH 4

Figure 1. Examples of biological activity chromenopyridines and targeted compounds.

The chromenopyridines, which are a combination of pyridines and chromenones, have a wide range of biological properties, including antitumour (Fig. 1, Compound A, B),15 antibacterial (Compound C),16 antipsychotic (Compound D), nervous system depressant (Fig. 1, schumanniophytine) chromenopyridines

and have

anti-inflammatory aroused

extensive

(Amlexanox)17 research

interest

effects.

Consequently,

among

chemists

and

pharmacologists. To date, assorted methods have been applied to the synthesis of chromenopyridine derivatives,18-23 these methods include the hetero-Diels-Alder reaction,18 intramolecular C–C bond coupling reactions, the coupling reactions of arylpropynyloxybenzonitriles with diaryliodonium triflates,19 [3+2+1] cycloaddition strategy,20 etc. The major building blocks, including 3-formylchromones,21 4-hydroxy-2H-chromen-2-one,22 4-chloro-2oxo-2H-chromene-3-carbalde-hyde,23

4-(arylamino)-2H-chro-men-2-one,24

3-benzoyl-4H-

chromen-4-one and chroman-4-one, have been used as substrates to construct chromenopyridine compounds. Although these methods have made important contribution to synthesis of chromenopyridines, they usually have some shortcomings, such as requiring high temperature, metal-catalyst, multi-steps, etc. Accordingly, a highly efficient and mild multicomponent one-pot cascade reaction for the synthesis of chromenopyridine derivatives is of interest, desirable and urgently needed.


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Our group used 3-formylchromones as the α,β-unsaturated aldehydes that use C1 as 1,4Michael acceptor and C4 as 1,2-addition acceptor to react with bis-nucleophilic reagents like HKAs for the synthesis of chromenopyridines possessing anticancer activity21a (Scheme 1). Khurana’s group used 3-formylchromones to provide C1 as 1,4-Michael acceptor and C4 as 1,2addition acceptor to react with EDAMs catalyzed by In(OTf)3 for the synthesis of chromenopyridines21b (Scheme 1). Recently, our group synthesized bicyclic pyridines21c using the cascade reaction of 3-formyl-chromones with HKAs (Scheme 1). Based on these research works, here, we report a concise, efficient and environment friendly method for the synthesis of novel highly functionalized 5H-chromeno[4,3-b]pyridines by a three-component, one-step cascade reaction (Scheme 1). Scheme 1. The synthetic routes of chromenopyridines

The three-component cascade reaction of 3-formylchromones, 1,1-enediamines and ethanol/amine proceeded in ethanol or acetone to produce chromeno[4,3-b] pyridines in moderate to good yields. Ethanol acts both as a substrate and a solvent. The three sites (C1, C3 and C4) of 3-formyl-chromones are concurrently present in the multicomponent cascade reactions. To the best of our knowledge, this is the first example of the synthesis of novel 5Hchromeno[4,3-b]pyridines by a three-component cascade reaction involving the three sites (C1, C3 and C4) of 3-formylchromones. This procedure, referred to as GAP chemistry, has many


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advantages, including convenience of operation, short reaction times, green solvent, and simple purification by washing the crude products with ethanol.

RESULTS AND DISCUSSION

To optimize the reaction conditions for the synthesis of 5H-chromeno[4,3-b]pyridines 4aa, 3Formylchromone 1a and (Z)-N-butyl-2-nitroethene-1,1-diamine 2a were used as substrates in the model reaction to determine the optimal reaction conditions. The different types and amounts of solvents, the temperature and the catalysts were carefully evaluated, and the results are shown in Table 1. First, the model reaction was investigated in six different solvents under refluxing treatment, the highest yield reached up to 64% in ethanol (Table 1, entry 3). Second, we performed the reaction at different temperatures in ethanol (Table 1, entries 3, 7–9). The results revealed that the reaction temperature had a considerable effect on the reaction and the yield of the target compound 4aa was 85% at 50 ℃ (Table 1, entry 10). Raising the temperature decreased the reaction time, but too low or too high temperature was unfavourable for the reaction (Table 1, entries 3, 7). Third, we also studied the amount of solvent and found that 4 mL of solvent is the optimum amount to obtain the highest yield of the target compound 4aa (Table 1, entries 8, 10, 11 and 12). Finally, the different acid catalysts including HClO4, acetic acid (HOAc), trifluoroacetic acid (TFA), methanesulfonic acid (MeSO3H) and HCl were evaluated, and it was discovered that HClO4 was the optimal catalyst to produce the best yields (Table 1, entries 10 vs. 13–16). Thus, the best reaction conditions for the synthesis of compound 4aa were: temperature under 50℃, for 24 h in 4 mL ethanol, to obtain a product yield of 85% (Table 1, entry 10). Based on the optimal reaction conditions, we further investigated the scope and generality of the cascade addition and condensation reactions of the 3-formylchromones with 1,1-enediamines.


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Table 1. Optimization of the reaction conditions for the model reactiona O

O

EtOH

+

O

NH2

BuHN

1a

a

N

H

O 2N H

NHBu NO 2

Solvent, Catalyst

3a

O OEt 4aa

2a

Entry

Solvent

Catalyst

T(°C)

t (minute)

Yieldb(%)

1

acetone (6 mL)

HClO4

reflux

24

56

2

THF (6 mL)

HClO4

reflux

24

52

3

EtOH (6 mL)

HClO4

reflux

24

64

4

CH3CN (6 mL)

HClO4

reflux

24

40

5

H2O (6 mL)

HClO4

reflux

24

28

6

1,4-dioxane (6 mL)

HClO4

reflux

24

51

7

EtOH (6 mL)

HClO4

40

24

63

8

EtOH (6 mL)

HClO4

50

24

84

9

EtOH (6 mL)

HClO4

60

24

78

10

EtOH (4 mL)

HClO4

50

24

85

11

EtOH (5 mL)

HClO4

50

24

84

12

EtOH (8 mL)

HClO4

50

24

81

13

EtOH (4 mL)

HOAc

50

24

79

14

EtOH (4 mL)

MeSO3Hc

50

24

64

15

EtOH (4 mL)

HCl

50

24

80

16

EtOH (4 mL)

TFA

50

24

81

Reaction conditions: 1a (0.5 mmol) and 2a (0.5 mmol) were dissolved in the EtOH (4

mL) and stired for many hours, then one drop of acid was added. b Isolated yield based on 1a. c MeSO3H (0.05 mmol).


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Different 3-formylchromones 1 and 1,1-enediamines 2 were used in this protocol (Table 2). First, chromone-3-carboxaldehyde 1a was used as substrate to react with different 1,1-enediamines 2a–2l (Table 2, entries 1–12). The results revealed that the substituted group on the 1,1enediamines 2 has only a slight influence on the yield, which did not lead us to find the obvious rules (Table 2, entries 1 and 3–12). However, the use of 2-nitroethene-1,1-diamine 2b as substrate to synthesize the product only led to the lowest yield (74%), the reactivity of the two amino groups of 2b maybe is the best and produce more byproducts. Second, the 6-fluoro-3formylchromone 1b reacted with 1,1-enediamines 2a and 2e–2l (Table 2, entries 13–21), the results indicated that the substituted group on the 1,1-enediamines 2 does not have a prominent influence on the yield (Table 2, entries 13–21). Finally, the other three 3-formylchromones 1c–1e were also used in this method. We also produced the target compounds with excellent yield (Table 2, entries 22–30). Overall, we conclude that the electron-drawing groups on the 3formylchromone 1 generally can produce higher yield than that of the electron-donating groups (1b, 1c > 1a> 1e) (Table 2, entries 1–12, 28–30 vs. 13–24). However, the NO2-substituented 3formylchromone 1d did not conform with this law and only produced lower yield (Table 2, entries 25–27 vs. 1–24 ＆ 28–30). After examining the participation of ethanol in this reaction, we wanted to test whether the other alcohols and amine compounds were compatible with this methodology. Accordingly, we conducted the reactions with a series of other alcohols and amines in acetone place of ethanol. The optimized conditions successfully produced the substituted 5H-chromeno[4,3-b]pyridines in good to excellent yield (Table 3, entries 1–7). This result demonstrates that this method for the synthesis of substituted 5H-chromeno[4,3-b]pyridines is viable for a variety of nucleophilic substrates 3b–3h (Table 3, entries 1–7).


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Table 2. The synthesis of 5H-chromeno[4,3-b]pyridines 4aa–4eka

Entry

1/R

2/R'

4

Yieldb (%)

1

1a/H

2a/n-butyl

4aa

85

2

1a/H

2b/H

4ab

74

3

1a/H

2c/cyclohexyl

4ac

83

4

1a/H

2d /4-Fphenyl

4ad

81

5

1a/H

2e/furan-2-ylmethyl

4ae

86

6

1a/H

2f/benzyl

4af

85

7

1a/H

2g/4-Fbenzyl

4ag

84

8

1a/H

2h/4-Clbenzyl

4ah

84

9

1a/H

2i/phenethyl

4ai

85

10

1a/H

2j/4-Fphenethyl

4aj

85

11

1a/H

2k/4-Clphenethyl

4ak

84

12

1a/H

2l/4-methoxyphenethyl

4al

85

13

1b/F

2a/n-butyl

4ba

87

14

1d/F

2e/furan-2-ylmethyl

4be

87

15

1b/F

2f/benzyl

4bf

91

16

1b/F

2g/4-Fbenzyl

4bg

89

17

1b/F

2h/4-Clbenzyl

4bh

88


9


a

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18

1b/F

2i/phenethyl

4bi

90

19

1b/F

2j/4-Fphenethyl

4bj

87

20

1b/F

2k/4-Clphenethyl

4bk

91

21

1b/F

2l/4-methoxyphenethyl

4bl

87

22

1c/Cl

2a/n-butyl

4ca

89

23

1c/Cl

2f/benzyl

4cf

90

24

1c/Cl

2i/phenethyl

4ci

89

25

1d/NO2

2a/n-butyl

4da

81

26

1d/NO2

2c/cyclohexyl

4dc

82

27

1d/NO2

2f/benzyl

4df

81

28

1e/Me

2c/cyclohexyl

4ec

80

29

1e/Me

2f/benzyl

4ef

82

30

1e/Me

2k/4-Fphenethyl

4ek

83

Reaction conditions: 1 (0.5 mmol) and 2 (0.5 mmol) were dissolved in the EtOH (4 mL) and

stired for 24 hours, then one drop of HClO4 was added. b Isolated yield based on 1.

A proposed mechanism for this cascade reaction is shown in Scheme 2. First, the α-C of 1,1enediamine 2 attacks the aldehyde group of the 3-formylchromone 1 to generate the intermediate 5 via a 1,2-addition reaction; this step has very high site-selectivity. Secondly, the intermediate 5 forms the intermediate 6 via an intramolecular 1,2-addition. Next, the intermediate 7 is obtained through the imine-enamine tautomerization of intermediate 6. The intermediate 7 received one proton to form the intermediate 8, which is followed by the loss of one molecule of water to produce the intermediate 9. Then, the intermediate 9 lost one molecule of water and underwent a


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Table 3. The synthesis of 5H-chromeno[4,3-b]pyridines 4a'–4g'a

a

Reaction conditions: 1a (0.5 mmol) and 2a (0.5 mmol) were dissolved in the acetone (4 mL) and stired for 24 hours, then 3 (0.6 mmol) and one drop of HClO4 was added. b Isolated yield based on 1.

carbonium ion rearrangement to give intermediate 10. Finally, intermediate 10 is attacked by the alkoxyl or alkyl amino to produce the final product 4. These results demonstrated that only one catalytic amount of HClO4 is required, and this reaction essentially completely environment friendly. It must be noted that the cascade reaction has very high regioselectivity. As a result, only the target product 4 and 4' was obtained under the current reaction conditions. Although the substrates are similar to those used by Poomathi (ref 21b), the mechanism of the reaction is completely different. Poomathi added the In(OTf)3 as catalyst at the beginning of the reaction, and 3-formylchromone and In(OTf)3 initially formed complex 3.21b Instead, in our work, First, the α-C of 1,1-enediamine 2 attacks the aldehyde group of the 3-formylchromone 1 to generate the intermediate 5 via a 1,2-addition reaction. Until the fourth step, as the intermediate 7 received one proton of HClO4 to form the intermediate 8 (Scheme 2). To prove this mechanism, we tried to make the mixture of 1a and 2a in ethanol at 50℃ for 12 h and subsequently one drop of HClO4 was added to the mixture. Then, we immediately injected


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the reaction mixture into the high-pressure liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) system. The molecular ion peak appeared in the high-resolution mass spectrometry (HRMS (TOF ES+): m/z calculated for C16H18N3O4 [M]+ as 316.1298 and found as 316.1292) (see supporting information, which is the HRMS spectra of intermediate 9). Scheme 2. Mechanism hypotheses for the synthesis of target compounds 4.

Products 4 were characterized by proton nuclear magnetic resonance (1H NMR),

13

C nuclear

magnetic resonance (13C NMR), Fourier transform infrared (FTIR) spectroscopy and HRMS. The results were all in agreement with the proposed structures. In order to further verify the structure of the substituted 5H-chromeno[4,3-b]pyridines, 4bg was selected as the representative compound and characterized by X-ray crystallography (see the supporting information: Figure S1, CCDC 1578705).

CONCLUSIONS In summary, we have developed an efficient three-component cascade reaction for the

preparation of novel 5H-chromeno[4,3-b]pyridines using environment friendly solvent and conditions. We use the GAP chemistry strategy, using only a simple filtration and washing the crude product to obtain the pure product. This approach minimizes solvent consumption by


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avoiding traditional purification techniques, such as column chromatography. This method is also an efficient and flexible route for the synthesis of a variety of 5H-chromeno[4,3-b]pyridines by the reaction of 3-formylchromone, 1,1-enediamines and alcohol or amine derivatives.

EXPERIMENTAL SECTION General Methods. All compounds were fully characterized by spectroscopic data. The NMR

spectra were recorded on a Bruker Avance (1H: 500 MHz, 13C: 125 MHz) or Bruker Avance (1H: 600 MHz,

13

C: 150 MHz), chemical shifts (δ) are expressed in ppm, and J values are given in

Hz, and deuterated CDCl3 and DMSO-d6 were used as solvent. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using KBr pellet. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF254. The melting points were determined on XT-4A melting point apparatus and are uncorrected. High resolution mass spectra (HRMS-TOF) were performed on AutoSpec Premier P776. X-ray diffraction was obtained by APEX DUO. All chemicals and solvents were used as received without further purification unless otherwise stated. Column chromatography was performed on silica gel (200–300 mesh). The materials were purchased from Adamas-beta. Compounds 2 were prepared according to the literature.25 General procedure for the synthesis of compounds 4aa–4ek. 3-Formylchromone 1 (0.5 mmol) was dissolved in ethanol (4 mL) and 1,1-enediamine 2 (0.5 mmol) was added to the mixture. The reaction mixture was stirred at 50°C until full consumption of 1,1-enediamine 2, which was observed by thin layer chromatography (TLC), then one drop of HClO4 was added. The resulting solvent was stirred for a further 10 min at 50°C and cooled to room temperature. The formed precipitate was then filtered and washed with ethanol to produce the pure products 4aa–4ek. The products were further identified by NMR spectroscopy, FTIR spectroscopy and


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HRMS. N-Butyl-5-ethoxy-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4aa). Yellow solid; yield: 146 mg, 85%; mp 91–93 °C; 1H NMR (500 MHz, CDCl3): δ = 1.00 (t, 3H, J = 3.5 Hz, CH3), 1.20 (t, 3H, J = 7.0 Hz, CH3), 1.46–1.50 (m, 2H, CH2),1.70–1.75 (m, 2H, CH2), 3.69–3.74 (m, 1H, OCH2), 3.76–3.82 (m, 2H, NCH2), 3.95–3.98 (m, 1H, OCH2), 6.05 (s, 1H, OCH), 7.06–7.08 (m, 1H, ArH), 7.13–7.17 (m, 1H, ArH), 7.42–7.46 (m, 1H, ArH), 8.24–8.26 (m, 1H, ArH), 8.36 (s, 1H, CH), 8.41 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 13.9, 15.1, 20.3, 31.4, 41.1, 64.2, 97.4, 114.5, 118.0, 120.7, 122.4, 126.0, 126.7, 133.2, 133.9, 152.5, 152.9, 154.5; IR (KBr): 3448, 3388, 1630, 1588, 1457, 1295, 1259, 1076, 1003, 772 cm-1; HRMS (TOF ESI+): m/z calcd. for C18H22N3O4 [M+H]+, 344.1605; found, 344.1606. 5-Ethoxy-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4ab). Yellow solid; yield: 106 mg, 74%; mp 141–143 °C; 1H NMR (500 MHz, CDCl3): δ = 1.22 (t, 3H, J = 7.0 Hz, CH3), 3.76–3.83 (m, 1H, OCH2), 3.95–4.00 (m, 1H, OCH2), 6.08 (s, 1H, OCH), 7.08 (d, 1H, J = 8.0 Hz, ArH), 7.14–7.17 (m, 1H, ArH), 7.44–7.47 (m, 1H, ArH), 8.22–8.23 (s, 1H, CH), 8.40 (m, 1H, ArH); 13

C NMR (125 MHz, CDCl3): δ = 15.1, 64.3, 97.2, 116.6, 118.0, 120.2, 122.6, 125.9, 127.0,

133.4, 133.7, 152.8, 153.7, 154.4; IR (KBr): 3439, 3370, 1626, 1607, 1504, 1292, 1254, 1077, 1004, 961, 771 cm-1; HRMS (TOF ESI+): m/z calcd. for C14H14N3O4 [M+H]+, 288.0979; found, 288.0979. N-Cyclohexyl-5-ethoxy-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine

(4ac).

Yellow

solid;

yield: 153 mg, 83%; mp 141–143 °C; 1H NMR (500 MHz, CDCl3): δ = 1.20 (t, 3H, J = 7.0 Hz, CH3), 1.32–1.56 (m, 5H, CH2), 1.68–1.70 (m, 1H, CH2),1.80–1.83 (m, 2H, CH2), 2.09–2.15 (m, 2H, CH2), 3.76–3.79 (m, 1H, OCH2), 3.95–3.98 (m, 1H, OCH2), 4.35–4.38 (m, 1H, NCH), 6.05 (s, 1H, OCH), 7.07 (d, 1H, J = 8.0 Hz, ArH), 7.14–7.17 (m, 1H, ArH), 7.43–7.46 (m, 1H, ArH),


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8.20–8.22 (m, 1H, ArH), 8.36 (br, 1H, NH), 8.37 (s, 1H, CH); 13C NMR (125 MHz, CDCl3): δ = 15.1, 24.7, 24.8, 25.8, 32.7, 32.8, 50.0, 64.2, 97.4, 114.4, 118.0, 120.8, 122.5, 125.9, 126.5, 133.2, 134.0, 152.1, 152.5, 154.5; IR (KBr): 3432, 1623, 1586, 1503, 1233, 1175, 1072, 767 cm1

; HRMS (TOF ESI+): m/z calcd. for C20H24N3O4 [M+H]+, 370.1761; found, 370.1761. 5-Ethoxy-N-(4-fluorophenyl)-3-nitro-5H-chromeno[4,3-b] pyridin-2-amine (4ad). Yellow

solid; yield: 154 mg, 81%; mp 177–179 °C; 1H NMR (500 MHz, CDCl3): δ = 1.22 (t, 3H, J = 7.0 Hz, CH3), 3.79–3.83 (m, 1H, OCH2), 3.96–4.01 (m, 1H, OCH2), 6.10 (s, 1H, OCH), 7.07– 7.15 (m, 4H, ArH), 7.44–7.46 (m, 1H, ArH), 7.65–7.67 (m, 2H, ArH), 8.06–8.08 (m, 1H, ArH), 8.48 (s, 1H, CH), 10.22 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 15.1, 64.4, 97.2, 115.6 (d, J = 21.3 Hz), 116.7, 118.1, 120.4, 122.7, 124.5 (d, J = 8.8 Hz), 126.2, 127.3, 133.6, 133.9, 134.2, 150.4, 152.5, 154.5, 159.9 (d, J = 243.8 Hz); IR (KBr): 3432, 2923, 1620, 1588, 1505, 1384, 1259, 1182, 1155, 1075 834, 767 cm-1; HRMS (TOF ESI+): m/z calcd. for C20H17FN3O4 [M+H]+, 382.1198; found, 382.1195. 5-Ethoxy-N-(furan-2-ylmethyl)-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine

(4ae).

Yellow

solid; yield: 158 mg, 86%; mp 162–164 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.0 Hz, CH3), 3.77–3.80 (m, 1H, OCH2), 3.96–3.99 (m, 1H, OCH2), 4.90–5.01 (m, 2H, NCH2), 6.06 (s, 1H, OCH), 6.33–6.34 (m, 2H, CH), 7.07 (m, 1H, ArH), 7.08–7.18 (m, 1H, ArH), 7.37–7.38 (m, 1H, CH), 7.44–7.47 (m, 1H, ArH), 8.28–8.30 (m, 1H, ArH), 8.39 (s, 1H, CH), 8.59–8.61 (m, 1H, NH);

13

C NMR (125 MHz, CDCl3): δ = 15.1, 38.3, 64.3, 97.3, 107.6, 110.5, 115.2, 118.0,

120.6, 122.5, 126.1, 127.2, 133.3, 133.9, 142.2, 151.5, 152.2, 152.3, 154.5; IR (KBr): 3394, 1620, 1584, 1305, 1289, 1174, 1005, 767, 600 cm-1; HRMS (TOF ESI+): m/z calcd. for C19H18N3O5 [M+H]+, 368.1241; found, 368.1240. N-Benzyl-5-ethoxy-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4af). Yellow solid; yield:


15


Page 16 of 33

160 mg, 85%; mp 140–142 °C; 1H NMR (600 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.1 Hz, CH3), 3.77–3.80 (m, 1H, OCH2), 3.95–3.98 (m, 1H, OCH2), 4.91–5.03 (m, 2H, NCH2), 6.06 (s, 1H, OCH), 7.06–7.07 (m, 1H, ArH), 7.12–7.14 (m, 1H, ArH), 7.25–7.45 (m, 6H, ArH), 8.21–8.23 (m, 1H, ArH), 8.40 (s, 1H, CH), 8.71 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ = 15.1, 45.3, 64.3, 97.3,115.1, 118.0, 120.6, 122.5, 126.1, 127.0, 127.5, 127.7, 128.8, 133.3, 134.0, 138.5, 152.5, 154.5; IR (KBr): 3400, 1621, 1585, 1295, 1278, 1177, 1110, 756, 602 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H20N3O4 [M+H]+, 378.1448; found, 378.1455. 5-Ethoxy-N-(4-fluorobenzyl)-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4ag). Yellow solid; yield: 166 mg, 84%; mp 172–174 °C; 1H NMR (600 MHz, CDCl3): δ = 1.13 (t, 3H, J = 7.1 Hz, CH3), 3.69–3.72 (m, 1H, OCH2), 3.89–3.91 (m, 1H, OCH2), 4.79–4.91 (m, 2H, NCH2), 5.99 (s, 1H, OCH), 6.94–7.08 (m, 4H, ArH), 7.29–7.32 (m, 2H, ArH), 7.36–7.39 (m, 1H, ArH), 8.11– 8.13 (m, 1H, ArH), 8.32 (s, 1H, CH), 8.62–8.63 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ = 15.1, 44.5, 64.4, 97.3, 115.2, 115.6 (d, J = 27.1 Hz), 118.1, 120.6, 122.5, 126.0, 127.0, 129.3 (d, J = 7.6 Hz), 133.4, 134.0, 134.3 (d, J = 3.0 Hz), 152.4, 152.5, 154.5, 162.2 (d, J = 244.5 Hz); IR (KBr): 3440, 1629, 1588, 1385, 1296, 1231, 1110, 1077, 767, 560 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H19FN3O4 [M+H]+, 396.1354; found, 396.1353. N-(4-Chlorobenzyl)-5-ethoxy-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine

(4ah).

Yellow

solid; yield: 173 mg, 84%; mp 162–164 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 5.6 Hz, CH3), 3.76–3.82 (m, 1H, OCH2), 3.94–4.00 (m, 1H, OCH2), 4.87–5.00 (m, 2H, NCH2), 6.07 (s, 1H, OCH), 7.06–7.07 (m, 1H, ArH), 7.08–7.15 (m, 1H, ArH), 7.30–7.36 (m, 4H, ArH), 7.43– 7.47 (m, 1H, ArH), 8.16–8.18 (m, 1H, ArH), 8.41 (s, 1H, CH), 8.71 (m, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 15.1, 44.6, 64.4, 97.3, 115.3, 118.0, 120.5, 122.5, 126.0, 127.1, 128.9, 129.0, 133.3, 133.4, 134.0, 137.1, 152.4, 152.5, 154.5; IR (KBr): 3343, 1654, 1586, 1348, 1384, 1275,


16

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1078, 800, 766 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H19ClN3O4 [M+H]+, 412.1059; found, 412.1054. 5-Ethoxy-9-fluoro-3-nitro-N-phenethyl-5H-chromeno[4,3-b]pyridin-2-amine

(4ai).

Yellow

solid; yield: 166 mg, 85%; mp 137–139 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 5.8 Hz, CH3), 3.02–3.07 (m, 2H, ArCH2), 3.75–3.81 (m, 1H, OCH2), 3.94–4.06 (m, 3H, OCH2, NCH2), 6.06 (s, 1H, OCH), 7.08 (d, 1H, J =7.1 Hz, ArH), 7.15–7.18 (m, 1H, ArH), 7.24–7.29 (m, 3H, ArH), 7.33–7.36 (m, 2H, ArH), 7.44–7.47 (m, 1H, ArH), 8.28–8.30 (m, 1H, ArH), 8.37 (s, 1H, CH), 8.44 (br, 1H, NH);

13

C NMR (125 MHz, CDCl3): δ = 15.1, 35.6, 42.9, 64.3, 97.4,

114.8, 118.0, 120.7, 122.5, 126.0, 126.6,, 126.9, 128.7, 128.8, 133.3, 133.9, 139.0, 152.5, 152.7, 154.5; IR (KBr): 3386, 1622, 1606, 1484, 1407, 1252, 1068, 1002, 956, 769, 700 cm-1; HRMS (TOF ESI+): m/z calcd. for C22H22N3O4 [M+H]+, 392.1605; found, 392.1604. 5-Ethoxy-N-(4-fluorophenethyl)-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4aj). Yellow solid; yield: 174 mg, 85%; mp 141–143 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.0 Hz, CH3), 3.00–3.03 (m, 2H, ArCH2), 3.77–3.80 (m, 1H, OCH2), 3.92–4.01(m, 3H, OCH2, NCH2), 6.06 (s, 1H, OCH), 7.00–7.09 (m, 3H, ArH), 7.15–7.18 (m, 1H, ArH), 7.22–7.25 (m, 2H, ArH), 7.44–7.48 (m, 1H, ArH), 8.25–8.27 (m, 1H, ArH), 8.37 (s, 1H, CH), 8.40–8.42 (br, 1H, NH);

13

C NMR (125 MHz, CDCl3): δ = 15.1, 34.8, 42.9, 64.3, 97.4, 114.9, 115.5 (d, J = 21.3

Hz), 118.1, 120.6, 122.5, 125.9, 126.9, 130.2 (d, J = 7.5 Hz), 133.3, 133.9, 134.6 (d, J = 2.5 Hz), 152.5, 152.6, 154.5, 161.8 (d, J = 243.8 Hz); IR (KBr): 3432, 3367, 1621, 1500, 1385, 1262, 1157, 1106, 1010, 915, 835, 767 cm-1; HRMS (TOF ESI+): m/z calcd. for C22H21FN3O4 [M+H]+, 410.1511; found, 410.1509. N-(4-Chlorophenethyl)-5-ethoxy-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4ak). Yellow solid; yield: 179 mg, 84%; mp 131–133 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.0


17


Page 18 of 33

Hz, CH3), 3.00–3.03 (m, 2H, ArCH2), 3.77–3.80 (m, 1H, OCH2), 3.94–4.01 (m, 3H, OCH2, NCH2), 6.06 (s, 1H, OCH), 7.08 (d, 1H, J = 0.60 Hz, ArH), 7.09–7.21 (m, 3H, ArH), 7.29–7.31 (m, 2H, ArH), 7.45–7.48 (m, 1H, ArH), 8.25–8.26 (m, 1H, ArH), 8.37 (s, 1H, CH), 8.42 (m, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 15.1, 35.0, 42.7, 64.3, 97.3, 114.9, 118.1, 120.6, 122.5, 125.9, 126.9, 128.9, 130.1, 132.5, 133.4, 134.0, 137.4, 152.5, 152.6, 154.5; IR (KBr): 3397, 1622, 1587, 1384, 1294, 1113, 1072, 766 cm-1; HRMS (TOF ESI+): m/z calcd. for C22H21ClN3O4 [M+H]+, 426.1215; found, 426.1215. 5-Ethoxy-N-(4-methoxyphenethyl)-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4al). Yellow solid; yield: 179 mg, 85%; mp 121–123 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.0 Hz, CH3), 2.96–3.00 (m, 2H, ArCH2), 3.76–3.80 (m, 4H, OCH3, OCH2), 3.94–4.00 (m, 3H, OCH2, NCH2), 6.06 (s, 1H, OCH), 6.88 (d, 2H, J = 8.5 Hz, ArH), 7.07–7.09 (m, 1H, ArH), 7.15– 7.21 (m, 3H, ArH), 7.44–7.46 (m, 1H, ArH), 8.27–8.29 (m, 1H, ArH), 8.37 (s, 1H, CH), 8.43 (br, 1H, NH);

13

C NMR (125 MHz, CDCl3): δ = 15.1, 34.7, 43.1, 55.3, 64.3, 97.4, 114.2, 114.7,

118.0, 120.7, 122.5, 126.0, 126.8, 129.7, 131.0, 133.3, 133.9, 152.5, 152.7, 154.5, 158.4; IR (KBr): 3425, 1621, 1585, 1384, 1248, 1169, 1112, 1078, 766 cm-1; HRMS (TOF ESI+): m/z calcd. for C23H24N3O5 [M+H]+, 422.1710; found, 422.1710. N-Butyl-5-ethoxy-9-fluoro-3-nitro-5H-chromeno[4,3-b]-pyridin-2-amine (4ba). Yellow solid; yield: 157 mg, 87%; mp 129–131 °C; 1H NMR (500 MHz, CDCl3): δ = 1.01 (t, 3H, J = 7.5 Hz, CH3), 1.21 (t, 3H, J = 7.5 Hz, CH3), 1.47–1.53 (m, 2H, CH2),1.70–1.76 (m, 2H, CH2), 3.69–3.76 (m, 1H, OCH2), 3.77–3.81 (m, 2H, NCH2), 3.92–3.97 (m, 1H, OCH2), 6.04 (s, 1H, OCH), 7.02– 7.05 (m, 1H, ArH), 7.13–7.17 (m, 1H, ArH), 7.89–7.92 (m, 1H, ArH), 8.39 (s, 1H, CH), 8.40 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 13.9, 15.1, 20.3, 31.3, 41.2, 64.4, 97.5, 111.7 (d, J = 25.0 Hz), 114.5 (d, J = 6.3 Hz), 119.3, 120.1(d, J = 31.3 Hz), 121.7 (d, J = 7.5 Hz), 127.1, 134.1,


18

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150.4, 151.7, 152.9, 158.17 (d, J = 245.0 Hz); IR (KBr): 3447, 1624, 1384, 1268, 1168, 1076 cm1

; HRMS (TOF ESI+): m/z calcd. for C18H21FN3O4 [M+H]+, 362.1511; found, 362.1505. 5-Ethoxy-N-(furan-2-ylmethyl)-3,9-dinitro-5H-chromeno[4,3-b]pyridin-2-amine (4be). Yellow

solid; yield: 168 mg, 87%; mp 154–156 °C; 1H NMR (500 MHz, CDCl3): δ = 1.20 (t, 3H, J = 7.0 Hz, CH3), 3.76–3.80 (m, 1H, OCH2), 3.94–3.97 (m, 1H, OCH2), 4.87–4.98 (m, 2H, NCH2), 6.04 (s, 1H, OCH), 6.33–6.35 (m, 2H, CH), 7.02–7.05 (m, 1H, CH), 7.13–7.17 (m, 1H, ArH), 7.39 (m, 1H, CH), 7.91–7.94 (m, 1H, ArH), 8.39–8.40 (m, 1H, ArH), 8.59–8.60 (br, 1H, NH);

13

C

NMR (125 MHz, CDCl3): δ = 15.0, 38.4, 64.4, 97.3, 107.6, 110.5, 111.7 (d, J = 25.0 Hz), 115.2, 119.3 (d, J = 7.5 Hz), 120.2 (d, J = 21.3 Hz), 121.6 (d, J = 8.8 Hz), 127.6, 134.0, 142.3, 150.4 (d, J = 1.3 Hz), 151.3, 151.4, 152.1, 158.2 (d, J = 240.0 Hz); IR (KBr): 3398, 1617, 1583, 1512, 1270, 1172, 1067, 1006, 934, 785, 747 cm-1; HRMS (TOF ESI+): m/z calcd. for C19H17FN3O5 [M+H]+, 386.1143; found, 386.1147. N-Benzyl-5-ethoxy-9-fluoro-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4bf). Yellow solid; yield: 180 mg, 91%; mp 154–156 °C; 1H NMR (600 MHz, DMSO-d6): δ = 1.20 (t, 3H, J = 7.1 Hz, CH3), 3.75–3.80 (m, 1H, OCH2), 3.92–3.98 (m, 1H, OCH2), 4.90–5.00 (m, 2H, NCH2), 6.05 (s, 1H, OCH), 7.02–7.04 (m, 1H, ArH), 7.12–7.15 (m, 1H, ArH), 7.25–7.42 (m, 5H, ArH), 7.84– 7.86 (m, 1H, ArH), 8.41 (s, 1H, CH), 8.71 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ = 15.0, 45.4, 64.4, 97.4, 111.7 (d, J = 24.0 Hz), 115.1, 119.27 (d, J = 9.0 Hz), 120.1 (d, J = 24.0 Hz), 121.6 (d, J = 7.6 Hz), 127.4, 127.6, 128.8, 134.1, 138.2, 150.4, 151.6 (d, J = 1.6 Hz), 152.5, 158.2 (d, J = 240.0 Hz); IR (KBr): 3422, 1621, 1589, 1384, 1237, 1167, 1073, 701 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H19FN3O4 [M+H]+, 396.1354; found, 396.1356. 5-Ethoxy-9-fluoro-N-(4-fluorobenzyl)-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine

(4bg).

Yellow solid; yield: 184 mg, 89%; mp 200–202 °C; 1H NMR (600 MHz, DMSO-d6): δ = 1.08 (t,


19


Page 20 of 33

3H, J = 7.0 Hz, CH3), 3.74–3.84 (m, 2H, OCH2), 4.87–4.88 (m, 2H, NCH2), 6.31 (s, 1H, OCH), 7.12–7.18 (m, 3H, ArH), 7.33–7.37 (m, 1H, ArH), 7.48–7.51 (m, 2H, ArH), 7.71–7.73 (m, 1H, ArH), 8.60 (s, 1H, CH), 9.21–9.23 (br, 1H, NH);

13

C NMR (150 MHz, DMSO-d6): δ = 15.4,

44.2, 64.1, 96.9, 111.1 (d, J = 24.0 Hz), 115.1, 115.5 (d, J = 21.0 Hz), 120.4 (d, J = 7.6 Hz), 120.7 (d, J = 24.0 Hz)， 121.7 (d, J = 7.6 Hz), 127.8, 129.6 (d, J = 9.0 Hz), 134.9, 136.3, 136.4, 150.5 (d, J = 30.0 Hz), 152.1, 157.8 (d, J = 237.0 Hz), 161.6 (d, J = 240.0 Hz); IR (KBr): 3394, 1616, 1588, 1483, 1267, 1170, 1109, 764, 562 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H18F2N3O4 [M+H]+, 414.1260; found, 414.1260. N-(4-Chlorobenzyl)-5-ethoxy-9-fluoro-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine

(4bh).

Yellow solid; yield: 189 mg, 88%; mp 186–188 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.0 Hz, CH3), 3.75–3.81 (m, 1H, OCH2), 3.92–3.98 (m, 1H, OCH2), 4.86–4.97 (m, 2H, NCH2), 6.06 (s, 1H, OCH), 7.02–7.05 (m, 1H, ArH), 7.13–7.17 (m, 1H, ArH), 7.32–7.36 (m, 4H, ArH), 7.79–7.82 (m, 1H, ArH), 8.42 (s, 1H, CH), 8.71 (br, 1H, NH);

13

C NMR (125 MHz,

CDCl3): δ = 15.0, 44.7, 64.5, 97.3, 111.7 (d, J = 25.0 Hz), 115.3, 119.4 (d, J = 7.5 Hz), 120.3 (d, J = 23.8 Hz), 121.5 (d, J = 7.5 Hz), 127.5, 128.9, 133.4, 134.1, 136.8, 150.4, 151.6, 152.4, 158.1 (d, J = 240 Hz); IR (KBr): 3432, 1617, 1483, 1384, 1338, 1169, 1074, 518 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H18ClFN3O4 [M+H]+, 430.0964; found, 430.0964. 5-Ethoxy-9-fluoro-3-nitro-N-phenethyl-5H-chromeno[4,3-b]pyridin-2-amine

(4bi). Yellow

solid; yield: 184 mg, 90%; mp 161–163 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.5 Hz, CH3), 3.03–3.05 (m, 2H, ArCH2), 3.75–3.81 (m, 1H, OCH2), 3.92–4.04 (m, 3H, OCH2, NCH2), 6.04 (s, 1H, OCH), 7.03–7.05 (m, 1H, ArH), 7.14–7.18 (m, 1H, ArH), 7.24–7.36 (m, 5H, ArH), 7.92–7.94 (m, 1H, ArH), 8.38 (s, 1H, CH), 8.42 (br, 1H, NH);

13

C NMR (125 MHz,

CDCl3): δ = 15.1, 35.6, 43.0, 64.4, 97.4, 111.7 (d, J = 23.8 Hz), 114.7, 119.3 (d, J = 7.5 Hz),


20

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120.1 (d, J = 23.8 Hz), 121.6, 126.7, 127.3, 128.8, 134.0, 138.8, 150.4, 151.6, 152.6, 158.2 (d, J = 238.8 Hz); IR (KBr): 3442, 1618, 1483, 1385, 1264, 1111, 988, 743, 698 cm-1; HRMS (TOF ESI+): m/z calcd. for C22H21FN3O4 [M+H]+, 410.1511; found, 410.1512. 5-Ethoxy-N-(4-fluorophenethyl)-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4bj). Yellow solid; yield: 186 mg, 87%; mp 158–160 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.5 Hz, CH3), 3.00–3.03 (m, 2H, ArCH2), 3.76–3.80 (m, 1H, OCH2), 3.93–4.00 (m, 3H, OCH2, NCH2), 6.05 (s, 1H, OCH), 7.01–7.06 (m, 3H, ArH), 7.14–7.18 (m, 1H, ArH), 7.22–7.26 (m, 2H, ArH), 7.90–7.92 (m, 1H, ArH), 8.39 (s, 1H, CH), 8.40 (br, 1H, NH);

13

C NMR (125 MHz,

CDCl3): δ = 15.0, 34.8, 42.9, 64.4, 97.4, 111.6 (d, J = 25.0 Hz), 114.8, 115.6 (d, J = 21.3 Hz), 119.4 (d, J = 7.5 Hz), 120.2 (d, J = 18.8 Hz), 121.6 (d, J = 8.8 Hz), 127.3, 130.2 (d, J = 7.5 Hz), 134.0, 134.5 (d, J = 3.8 Hz), 150.4 (d, J = 1.3 Hz), 151.6 (d, J = 2.5 Hz), 152.6, 158.1 (d, J = 7.5 Hz), 161.8 (d, J = 242.5 Hz); IR (KBr): 3432, 3365, 1618, 1592, 1511, 1484, 1385, 1265, 1101, 1088, 986, 838 cm-1; HRMS (TOF ESI+): m/z calcd. for C22H20F2N3O4 [M+H]+, 428.1416; found, 428.1415. N-(4-Chlorophenethyl)-5-ethoxy-9-fluoro-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4bk). Yellow solid; yield: 202 mg, 91%; mp 140–142 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.5 Hz, CH3), 3.00–3.03 (m, 2H, ArCH2), 3.77–3.81 (m, 1H, OCH2), 3.93–4.02 (m, 3H, OCH2, NCH2), 6.05 (s, 1H, OCH), 7.04–7.06 (m, 1H, ArH), 7.15–7.22 (m, 3H, ArH), 7.30–7.32 (m, 2H, ArH), 7.89–7.92 (m, 1H, ArH), 8.39–8.40 (m, 1H, CH), 8.43 (br, 1H, NH);

13

C NMR

(125 MHz, CDCl3): δ = 15.1, 35.0, 42.8, 64.4, 97.4, 111.6 (d, J = 25.0 Hz), 114.9, 119.4 (d, J = 7.5 Hz), 120.2 (d, J = 23.8 Hz), 121.6, 127.3, 128.9, 130.1, 132.6, 134.1, 137.3, 150.4, 151.6, 152.6, 158.2 (d, J = 240.0 Hz); IR (KBr): 3439, 1618, 1589, 1384, 1268, 1167, 1112, 1071, 986, 883 cm-1; HRMS (TOF ESI+): m/z calcd. for C22H20ClFN3O4 [M+H]+, 444.1121; found,


21


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444.1119. 5-Ethoxy-9-fluoro-N-(4-methoxyphenethyl)-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4bl). Yellow solid; yield: 191 mg, 87%; mp 127–129 °C; 1H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3H, J = 7.0 Hz, CH3), 2.96–3.00 (m, 2H, ArCH2), 3.76–3.79 (m, 4H, OCH3, OCH2), 3.93–4.98 (m, 3H, OCH2, NCH2), 6.04 (s, 1H, OCH), 6.87–6.89 (m, 2H, ArH), 7.02–7.05 (m, 1H, ArH), 7.14–7.21 (m, 3H, ArH), 7.91–7.93 (m, 1H, ArH), 8.38 (s, 1H, CH), 8.41 (br, 1H, NH);

13

C

NMR (125 MHz, CDCl3): δ = 15.1, 34.7, 43.2, 55.3, 64.4, 97.4, 111.7 (d, J = 25.0 Hz), 114.2, 114.7, 119.3 (d, J = 8.8 Hz), 120.1 (d, J = 23.8 Hz), 121.7 (d, J = 8.8 Hz), 127.2, 129.7, 130.8, 134.0, 150.4 (d, J = 1.3 Hz), 151.6, 152.6, 158.1 (d, J = 240.0 Hz), 158.5; IR (KBr): 3415, 1618, 1586, 1513, 1485, 1269, 1246, 1168, 1071, 817, 781 cm-1; HRMS TOF (ESI+): m/z calcd. for C23H23FN3O5 [M+H]+, 440.1616; found, 440.1617. N-Butyl-9-chloro-5-ethoxy-3-nitro-5H-chromeno[4,3-b] pyridin-2-amine (4ca). Yellow solid; yield: 168 mg, 89%; mp 136–138 °C; 1H NMR (500 MHz, CDCl3): δ = 1.02 (t, 3H, J = 7.5 Hz, CH3), 1.21 (t, 3H, J = 7.5 Hz, CH3), 1.46–1.53 (m, 2H, CH2),1.71–1.77 (m, 2H, CH2), 3.70– 3.3.74 (m, 1H, OCH2), 3.75–3.81 (m, 2H, NCH2), 3.92–3.97 (m, 1H, OCH2), 6.05 (s, 1H, OCH), 7.02 (d, 1H, J = 9.0 Hz, ArH), 7.37–7.39 (m, 1H, ArH), 8.18 (d, 1H, J = 3.0 Hz, ArH), 8.38 (s, 1H, CH), 8.40 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 13.8, 15.0, 20.3, 31.3, 41.2, 64.4, 97.5, 114.3, 119.5, 121.9, 125.5, 127.1, 127.7, 132.8, 134.1, 151.2, 152.8, 152.9; IR (KBr): 3386, 1624, 1589, 1540, 1385, 1263, 1076, 817, 780 cm-1; HRMS (TOF ESI+): m/z calcd. for C18H21ClN3O4 [M+H]+, 378.1215; found, 378.1218. N-Benzyl-9-chloro-5-ethoxy-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4cf). Yellow solid; yield: 185 mg, 90%; mp 157–159 °C; 1H NMR (600 MHz, CDCl3): δ = 1.20 (t, 3H, J = 7.1 Hz, CH3), 3.76–3.80 (m, 1H, OCH2), 3.92–3.96 (m, 1H, OCH2), 4.89–4.99 (m, 2H, NCH2), 6.05 (s,


22

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1H, OCH), 7.00–7.01 (m, 1H, J = 8.7 Hz, ArH), 7.25–7.43 (m, 6H, ArH), 8.12 (d, 1H, J = 2.5 Hz, ArH), 8.40 (s, 1H, CH), 8.70 (s, 1H, ArH);

13

C NMR (150 MHz, CDCl3): δ = 15.0, 45.5,

64.5, 97.4, 114.9, 119.5, 121.8, 125.6, 127.4, 127.6, 127.7, 127.8, 128.8, 132.9, 134.1, 138.2, 151.2, 152.4, 152.9; IR (KBr): 3340, 1623, 1587, 1479, 1385, 1340, 1178, 1075 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H19ClN3O4 [M+H]+, 412.1059; found, 412.1066. 9-Chloro-5-ethoxy-3-nitro-N-phenethyl-5H-chromeno[4,3-b]pyridin-2-amine

(4ci).

Yellow

solid; yield: 190 mg, 89%; mp 165–167 °C; 1H NMR (500 MHz, CDCl3): δ = 1.20 (t, 3H, J = 7.0 Hz, CH3), 3.02–3.06 (m, 2H, ArCH2), 3.76–3.80 (m, 1H, OCH2), 3.92–4.02 (m, 3H, OCH2, NCH2), 6.05 (s, 1H, OCH), 7.02 (d, 1H, J = 9.0 Hz, ArH), 7.24–7.40 (m, 6H, ArH), 8.22–8.23 (m, 1H, ArH), 8.37 (s, 1H, CH), 8.42–8.44 (m, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 15.1, 35.6, 43.1, 64.5, 97.5, 114.6, 119.5, 121.9, 125.5, 126.7, 127.3, 127.8, 128.8, 132.9, 134.1, 138.8, 151.2, 152.6, 152.9; IR (KBr): 3407, 1621, 1585, 1479, 1385, 1264, 1111, 1074, 814, 702 cm-1; HRMS (TOF ESI+): m/z calcd. for C22H21ClN3O4 [M+H]+, 426.1215; found, 426.1217. N-Butyl-5-ethoxy-3,9-dinitro-5H-chromeno[4,3-b]pyrid-ine-2-amine (4da). Yellow solid; yield: 157 mg, 81%; mp 168–170 °C; 1H NMR (500 MHz, CDCl3): δ = 1.03 (t, 3H, J = 7.0 Hz, CH3), 1.23 (t, 3H, J = 7.5 Hz, CH3), 1.49–1.56 (m, 2H, CH2), 1.73–1.79 (m, 2H, CH2), 3.74–3.86 (m, 3H, OCH2, NCH2), 3.97–4.02 (m, 1H, OCH2), 6.18 (s, 1H, OCH), 7.18 (d, 1H, J = 10.8 Hz, ArH), 8.30–8.32 (m, 1H, ArH), 8.42 (br, 1H, NH), 8.43 (s, 1H, CH), 9.11 (d, 1H, J = 3.0 Hz, ArH);

13

C NMR (125 MHz, CDCl3): δ = 13.8, 15.0, 20.3, 31.2, 41.3, 65.0, 98.2, 113.8, 118.9,

120.9, 122.1, 127.6, 127.8, 134.3, 143.1, 150.2, 152.8, 158.9; IR (KBr): 3346, 1627, 1586, 1522, 1341, 1221, 1092, 961 cm-1; HRMS (TOF ESI+): m/z calcd. for C18H21N4O6 [M+H]+, 389.1456; found, 389.1456. N-Cyclohexyl-5-ethoxy-3,9-dinitro-5H-chromeno[4,3-b]pyridin-2-amine (4dc). Yellow solid;


23


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yield: 170 mg, 82%; mp 219–221 °C; 1H NMR (500 MHz, CDCl3): δ = 1.23 (t, 3H, J = 7.0 Hz, CH3), 1.37–1.71 (m, 6H, CH2), 1.81–1.86 (m, 2H, CH2), 2.21–2.33 (m, 2H, CH2), 3.81–3.85 (m, 1H, OCH2), 3.98–4.02 (m, 1H, OCH2), 4.37–4.39 (m, 1H, NCH), 6.18 (s, 1H, OCH), 7.18–7.19 (d, 1H, J = 9.0 Hz, ArH), 8.30–8.32 (m, 1H, ArH), 8.37 (d, 1H, J = 8.0 Hz, NH), 8.43 (s, 1H, CH), 9.07–9.08 (m, 1H, ArH);

13

C NMR (125 MHz, CDCl3): δ = 15.0, 24.5, 24.6, 25.7, 32.5,

32.6, 50.3, 65.0, 98.3, 113.6, 118.9, 120.9, 122.1, 127.4, 127.8, 134.4, 143.1, 150.2, 152.0, 158.9; IR (KBr): 3439, 3371, 1624, 1588, 1521, 1343, 1074, 956, 780, 605 cm-1; HRMS (TOF ESI+): m/z calcd. for C20H23N4O6 [M+H]+, 415.1612; found, 415.1613. N-Benzyl-5-ethoxy-3, 9-dinitro-5H-chromeno[4,3-b]pyridin-2-amine (4df) . Yellow solid; yield: 171 mg, 81%; mp 186–188 °C; 1H NMR (600 MHz, CDCl3): δ = 1.22 (t, 3H, J = 7.1 Hz, CH3), 3.81–3.85 (m, 1H, OCH2), 3.96–4.00 (m, 1H, OCH2), 4.91–4.99 (m, 2H, NCH2), 6.18 (s, 1H, OCH), 7.16–7.17 (d, 1H, J = 9.0 Hz, ArH), 7.26–7.30 (m, 1H, ArH), 7.37–7.40 (m, 2H, ArH), 7.47–7.48 (m, 2H, ArH), 8.28–8.30 (m, 1H, ArH), 8.45 (s, 1H, CH), 8.76–8.79 (m, 1H, NH), 9.05–9.06 (m, 1H, ArH);

13

C NMR (150 MHz, CDCl3): δ = 15.0, 45.8, 65.0, 98.2, 114.4,

118.8, 120.8, 122.3, 127.6, 127.7, 127.8, 128.0, 128.9, 134.3, 138.1, 143.1, 150.2, 152.5, 158.8; IR (KBr): 3396, 1625, 1584, 1518, 1335, 1274, 1071, 948, 754 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H19N4O6 [M+H]+, 423.1299; found, 423.1302. N-Cyclohexyl-5-ethoxy-9-methyl-3-nitro-5H-chromeno[4, 3-b]pyridin-2-amine (4ec). Yellow solid; yield: 153 mg, 80%; mp 183–185 °C; 1H NMR (500 MHz, CDCl3): δ = 1.20 (t, 3H, J = 7.0 Hz, CH3), 1.34–1.54 (m, 5H, CH2), 1.68–1.70 (m, 1H, CH2),1.81–1.83 (m, 2H, CH2), 2.09– 2.16 (m, 2H, CH2), 2.40 (s, 3H, CH3), 3.74–3.78 (m, 1H, OCH2), 3.93–3.96 (m, 1H, OCH2), 4.37–4.39 (m, 1H, NCH), 6.02 (s, 1H, OCH), 6.97 (d, 1H, J = 9.5 Hz, ArH), 7.24–7.26 (m, 1H, ArH), 7.98 (s, 1H, CH), 8.36 (m, 1H, ArH), 8.39 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ =


24

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15.1, 20.9, 24.6, 24.7, 25.8, 32.6, 32.7, 49.9, 64.1, 97.4, 114.6, 117.8, 120.4, 125.9, 126.4, 131.8, 133.9, 134.1, 152.1, 152.5, 152.7; IR (KBr): 3432, 2925, 1610, 1584, 1484, 1244, 1071, 983, 815, 545 cm-1; HRMS (TOF ESI+): m/z calcd. for C21H26N3O4 [M+H]+, 384.1918; found, 384.1919. N-Benzyl-5-ethoxy-9-methyl-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4ef). Yellow solid; yield: 160 mg, 82%; mp 154–156 °C; 1H NMR (600 MHz, CDCl3): δ = 1.20 (t, 3H, J = 7.1 Hz, CH3), 2.37 (s, 3H, ArCH3), 3.75–3.78 (m, 1H, OCH2), 3.93–3.96 (m, 1H, OCH2), 4.91–5.04 (m, 2H, NCH2), 6.03 (s, 1H, OCH), 6.95–6.97 (m, 1H, J = 8.0 Hz, ArH), 7.24–7.44 (m, 6H, ArH), 7.97 (s, 1H, ArH), 8.39 (s, 1H, CH), 8.72 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ = 15.1, 20.8, 45.4, 64.2, 97.3, 115.3, 117.8, 120.3, 126.0, 126.9, 127.5, 127.7, 128.8, 131.9, 133.9, 134.2, 138.6, 152.4, 125.5, 152.7; IR (KBr): 3395, 1625, 1587, 1485, 1384, 1275, 1178, 1074, 814, 695 cm-1; HRMS (TOF ESI+): m/z calcd. for C22H22N3O4 [M+H]+, 392.1605; found, 392.1608. 5-Ethoxy-N-(4-fluorophenethyl)-9-methyl-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4ek). Yellow solid; yield: 176 mg, 83%; mp 170–172 °C; 1H NMR (600 MHz, CDCl3): δ = 1.20 (t, 3H, J = 7.1 Hz, CH3), 2.41 (s, 3H, CH3), 3.00–3.04 (m, 2H, ArCH2), 3.75–3.78 (m, 1H, OCH2), 3.92–4.02 (m, 3H, OCH2, NCH2), 6.03 (s, 1H, OCH), 6.98–7.04 (m, 3H, ArH), 7.25–7.28 (m, 3H, ArH), 8.05 (s, 1H, ArH), 8.36 (s, 1H, CH), 8.44 (br, 1H, NH); 13C NMR (150 MHz, CDCl3): δ = 15.1, 20.9, 34.8, 43.0, 64.2, 97.3, 115.1, 115.6 (d, J = 21.0 Hz), 117.9, 120.3, 125.8, 126.8, 130.2 (d, J = 7.5 Hz), 131.8, 133.9, 134.3, 134.7 (d, J = 3.0 Hz), 152.5, 152.6, 161.8 (d, J = 243.0 Hz); IR (KBr): 3432, 1626, 1611, 1508, 1481, 1252, 1168, 1069, 819, 787 cm-1; HRMS (TOF ESI+): m/z calcd. for C23H23FN3O4 [M+H]+, 424.1667; found, 424.1673. General procedure for the synthesis of compounds 4a'–4g'. 3-Formylchromone 1 (0.5 mmol) was dissolved in acetone (4 mL) and 1,1-enediamine 2 (0.5 mmol) was added to the


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mixture. The reaction mixture was stirred at 50°C until full consumption of 1,1-enediamine 2, which was observed by thin layer chromatography (TLC), then alcohol or amine 3 (0.6 mmol) and one drop of HClO4 were added. The resulting solvent was stirred for a further 10 min at 50°C and cooled to room temperature. The formed precipitate was then filtered and washed with ethanol to produce the pure products 4a'–4g'. N-Butyl-5-methoxy-3-nitro-5H-chromeno[4,3-b]pyridin-2-amine (4a'). Yellow solid; yield: 152 mg, 92%; mp 97–99 °C; 1H NMR (500 MHz, CDCl3): δ = 1.00 (t, 3H, J = 7.5 Hz, CH3), 1.46–1.51 (m, 2H, CH2), 1.70–1.74 (m, 2H, CH2), 3.56 (s, 3H, CH3), 3.71–3.80 (m, 2H, NCH2), 5.94 (s, 1H, OCH), 7.10 (d, 1H, J = 8.5 Hz, ArH), 7.15–7.18 (m, 1H, ArH), 7.44–7.47 (m, 1H, ArH), 8.25 (d, 1H, J = 8.0 Hz, ArH), 8.37 (s, 1H, CH), 8.41 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 13.9, 20.3, 31.4, 41.1, 55.8, 98.5, 114.3, 118.0, 120.7, 122.6, 126.0, 126.7, 133.3, 134.0, 152.4, 152.9, 154.3; IR (KBr): 3396, 1620, 1406, 1292, 1207, 1077, 1013, 922, 768, 599 cm-1; HRMS (TOF ESI+): m/z calcd. for C17H20N3O4 [M+H]+, 330.1448; found, 330.1451. N-Butyl-3-nitro-5-propoxy-5H-chromeno[4,3-b]pyridin-2 -amine (4b'). Yellow solid; yield: 161 mg, 90%; mp 98–100 °C; 1H NMR (500 MHz, CDCl3): δ = 0.86 (t, 3H, J = 7.5 Hz, CH3), 1.00 (d, 3H, J = 7.5 Hz, CH3), 1.45–1.52 (m, 2H, CH2), 1.56–1.62 (m, 2H, CH2), 1.71–1.76 (m, 2H, CH2), 3.66–3.89 (m, 4H, NCH2, OCH2), 6.04 (s, 1H, OCH), 7.07 (d, 1H, J = 8.5 Hz, ArH), 7.13–7.17 (m, 1H, ArH), 7.43–7.46 (m, 1H, ArH), 8.26 (d, 1H, J = 8.0 Hz, ArH), 8.37 (s, 1H, CH), 8.42 (br, 1H, NH);

13

C NMR (125 MHz, CDCl3): δ = 10.5, 13.9, 20.3, 22.8, 31.4, 41.1,

70.4, 97.6, 114.6, 118.0, 120.8, 122.4, 126.0, 126.7, 133.2, 133.9, 152.6, 152.9, 154.5; IR (KBr): 3398, 2925, 1624, 1608, 1586, 1330, 1293, 1190, 1029, 964, 765 cm-1; HRMS (TOF ESI+): m/z calcd. for C19H24N3O4 [M+H]+, 358.1761; found, 358.1759. N-Butyl-5-isopropoxy-3-nitro-5H-chromeno[4,3-b]pyrid-ine-2-amine (4c').

Yellow solid;


26

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yield: 159 mg, 89%; mp 104–106 °C; 1H NMR (500 MHz, CDCl3): δ = 1.00 (t, 3H, J = 7.0 Hz, CH3), 1.17 (d, 3H, J = 6.0 Hz, CH3), 1.27 (d, 3H, J = 6.5 Hz, CH3), 1.44–1.50 (m, 2H, CH2), 1.70–1.76 (m, 2H, CH2), 3.69–3.74 (m, 1H, NCH2), 3.77–3.82 (m, 1H, NCH2), 4.24–4.27 (m, 1H, OCH), 6.13 (s, 1H, OCH), 7.04–7.06 (m, 1H, J = 8.0 Hz, ArH), 7.13–7.16 (m, 1H, ArH), 7.43–7.46 (m, 1H, ArH), 8.24–8.26 (d, 1H, J = 8.0 Hz, ArH), 8.32 (s, 1H, CH), 8.41 (br, 1H, NH);

13

C NMR (125MHz, CDCl3): δ = 13.9, 20.3, 22.0, 23.3, 31.4, 41.1, 70.9, 96.0, 114.9,

118.0, 120.8, 122.3, 126.0, 126.7, 133.2, 133.7, 152.6, 152.8, 154.6; IR (KBr): 3395, 2966, 1621, 1607, 1506, 1343, 1257, 1234, 1053, 1002, 916, 766 cm-1; HRMS (TOF ESI+): m/z calcd. for C19H24N3O4 [M+H]+, 358.1761; found, 358.1760. 5-(Benzyloxy)-N-butyl-3-nitro-5H-chromeno[4,3-b]pyrid-in-2-amine (4d'). Yellow solid; yield: 172 mg, 85%; mp 119–121 °C; 1H NMR (500 MHz, CDCl3): δ = 0.99 (t, 3H, J = 7.0 Hz, CH3), 1.44–1.51 (m, 2H, CH2), 1.69–1.75 (m, 2H, CH2), 3.68–3.73 (m, 1H, NCH2), 3.75–3.81 (m, 1H, NCH2), 4.78–4.88 (m, 2H, OCH2), 6.09 (s, 1H, OCH), 7.05–7.06 (d, 1H, J = 8.0 Hz, ArH), 7.14– 7.17 (m, 1H, ArH), 7.30–7.34 (m, 5H, ArH), 7.43–7.46 (m, 1H, ArH), 8.25 (d, 1H, J = 8.0 Hz, ArH), 8.29 (s, 1H, CH), 8.40 (br, 1H, NH);

13

C NMR (125 MHz, CDCl3): δ = 13.9, 20.3, 31.4,

41.1, 70.0, 96.3, 114.3, 118.0, 120.8, 122.6, 126.0, 126.7, 128.1, 128.2, 128.6, 133.2, 133.9, 136.9, 152.5, 152.9, 154.3; IR (KBr): 3402, 2930, 1623, 1608, 1512, 1317, 1292, 1208, 1186, 1150, 923, 767, 699 cm-1; HRMS (TOF ESI+): m/z calcd. for C23H24N3O4 [M+H]+, 406.1761; found, 406.1761. N2-Butyl-3-nitro-N5-propyl-5H-chromeno[4,3-b]pyridine-2,5-diamine (4e'). Yellow solid; yield: 163 mg, 88%; mp 98–100 °C; 1H NMR (500 MHz, CDCl3): δ = 0.92 (t, 3H, J = 7.0 Hz, CH3), 1.00 (t, 3H, J = 7.0 Hz, CH3), 1.32–1.39 (m, 2H, CH2), 1.44–1.56 (m, 4H, CH2), 1.70–1.76 (m, 2H, CH2), 2.13 (br, 1H, NH), 2.82–2.87 (m, 1H, NCH2), 2.98–3.03 (m, 1H, NCH2), 3.74–


27


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3.77 (m, 2H, NCH2), 5.85 (s, 1H, CH), 7.00 (d, 1H, J = 8.0 Hz, ArH), 7.07–7.10 (m, 1H, ArH), 7.40–7.43 (m, 1H, ArH), 8.18–8.19 (m, 1H, ArH), 8.39 (br, 1H, NH); 8.41 (s, 1H, CH),

13

C

NMR (125 MHz, CDCl3): δ = 13.9, 20.3, 31.5, 32.4, 41.1, 44.7, 87.5, 116.9, 118.2, 121.1, 121.8, 126.1, 126.8, 133.4, 133.5, 152.5, 153.6, 156.1; IR (KBr): 3368, 3331, 2956, 1621, 1602, 1494, 1478, 1256, 1225, 1184, 765, 750 cm-1; HRMS (TOF ESI+): m/z calcd. for C20H27N4O3 [M+H]+, 371.2078; found, 371.2076. N2-Butyl-3-nitro-N5-phenyl-5H-chromeno[4,3-b]pyridine-2,5-diamine (4f'). Yellow solid; yield: 166 mg, 85%; mp 158–160 °C; 1H NMR (500 MHz, CDCl3): δ = 1.01 (t, 3H, J = 7.0 Hz, CH3), 1.46–1.52 (m, 2H, CH2), 1.72–1.77 (m, 2H, CH2), 3.76–3.77 (m, 2H, NCH2), 4.67 (d, 1H, J = 9.0 Hz, NH), 6.52 (d, 1H, J = 9.5 Hz, OCH), 6.87–6.91 (m, 3H, ArH), 6.95–6.97 (m, 1H, ArNH), 7.09–7.12 (m, 1H, ArH), 7.24–7.27 (m, 2H, ArH), 7.36–7.39 (m, 1H, ArH), 8.20–8.21 (m, 1H, ArH), 8.38 (s, 1H, CH), 8.41 (br, 1H, NH); 13C NMR (125 MHz, CDCl3): δ = 13.9, 20.3, 31.5, 41.2, 81.5, 114.8, 115.3, 118.7, 120.3, 120.9, 122.3, 126.0, 126.7, 129.4, 133.3, 133.5, 144.1, 152.7, 153.3, 155.4; IR (KBr): 3393, 1624, 1604, 1591, 1501, 1279, 1247, 1183, 1127, 767, 751 cm-1; HRMS (TOF ESI-): m/z calcd. for C22H21N4O3 [M-H]-, 389.1619; found, 389.1620. N5-Benzyl-N2-butyl-3-nitro-5H-chromeno[4,3-b]pyridine-2,5-diamine (4g'). Yellow solid; yield: 162 mg, 80%; mp 77–79 °C; 1H NMR (500 MHz, CDCl3): δ = 1.00 (t, 3H, J = 7.0 Hz, CH3), 1.45–1.52 (m, 2H, CH2), 1.69–1.75 (m, 2H, CH2), 3.72–3.76 (m, 2H, NCH2), 4.07–4.14 (m, 2H, ArCH2N), 5.85 (s, 1H, OCH), 7.02 (d, 1H, J = 8.5 Hz, ArH), 7.08–7.11 (m, 1H, ArH), 7.25–7.43 (m, 6H, ArH), 8.17–8.18 (d, 1H, J = 8.0 Hz, ArH), 8.38 (br, 1H, NH); 8.42 (s, 1H, CH),13C NMR (125 MHz, CDCl3): δ = 13.9, 20.3, 31.5, 41.1, 48.8, 86.4, 116.6, 118.2, 121.1, 121.9, 126.1, 126.8, 127.3, 128.3, 128.5, 133.4, 139.2, 152.6, 153.5, 155.9; IR (KBr): 3397,


28

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2952, 1621, 1603, 1521, 1284, 1201, 1004, 765, 697 cm-1; HRMS (TOF ESI+): m/z calcd. for C23H25N4O3 [M+H]+, 405.1921; found, 405.1926.

ASSOCIATED CONTENT

Supporting Information Spectroscopic and analytical data as well as the original copy of 1H and 13C NMR spectra of all new compounds and X-ray crystallographicdata (CIF file) of compound 4bg (CCDC 1578705). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Authors *E-mail: [email protected] (J. L) *E-mail: [email protected] (S.-J. Y). Tel/Fax: +86 87165031633. ORCID Jun Lin: 0000-0002-2087-6013. Sheng-Jiao Yan: 0000-0002-7430-4096 Notes The authors declare no competing financial interest.

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).

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Three-component site-selective synthesis of highly substituted 5H

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