Highly selective synthesis of 2-amino-4,6-diarylpyridine derivatives by

Subscriber access provided by Iowa State University | Library

Article

Highly selective synthesis of 2-amino-4,6-diarylpyridine derivatives by the cascade reaction of 1,1-enediamines with #,#-unsaturated ketones Qin Luo, Rong Huang, Qiang Xiao, Yuan Yao, Jun Lin, and Sheng-Jiao Yan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03008 • Publication Date (Web): 17 Jan 2019 Downloaded from http://pubs.acs.org on January 17, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Highly

selective

synthesis

of

2-amino-4,6-

diarylpyridine derivatives by the cascade reaction of 1,1-enediamines with α,β-unsaturated ketones Qin Luo,‡,† Rong Huang, ‡,† Qiang Xiao,† Yuan Yao,† Jun Lin*,† and Sheng-Jiao Yan*,† †

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of

Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China.

KEYWORDS: pyridine derivatives, the cascade reaction, 1,1-enediamines, α,β-unsaturated ketones, selective synthesis

ACS Paragon Plus Environment

1

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 41

ABSTRACT: A general and concise method was developed for the synthesis of 2-amino-4,6diarylpyridine derivatives 4–6 through the cascade reaction, which includes the Michael addition, intramolecular cyclization, aromatization and/or loss of HNO2, of different types of α,βunsaturated ketones 1 and 1,1-enediamines 2–3 in 1,4-dioxane promoted by the base Cs2CO3 or piperidine. This method is suitable for the efficient parallel synthesis of pyridines. A library of highly functional 2-amino-4,6-diarylpyridine derivatives was easily constructed using the cascade reaction described in this study.


2

Page 3 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60




INTRODUCTION The aryl-substituted 2-aminopyridine derivatives are one of the important classes of nitrogen

heterocyclic compounds and are also ubiquitous structural motifs in biologically active molecules. This kind of compounds possess broad spectrum biologically activity including anticancer,1 treatment of neurodegeneration,2 allosteric BCRABL1 inhibitor,3 treatment of resistant fungal infections,4 etc. Up to date, various protocols have been developed to synthesis of aryl-substituted 2-aminopyridines.5-7 The classic method to this compound is transition metalcatalyzed amination of aryl halides, typically including palladium-catalyzed Buchwald-Hartwig amination6 and copper-catalyzed Ullmann-type amination.7 Among of them, the 2-amino-4,6diarylpyridine derivatives (ADPDs) are great important that rooted in their interesting biologically such as A2A adenosine receptor antagonist,8 Serotonnin-5-HT2A receptor,9 vasodilation potency10 and anti-inflammatory agent11 (Figure 1). As a result, various methods for

Figure 1. Bioactive 2-amino-4,6-diarylpyridine derivatives and the target compounds.


3


Page 4 of 41

ADPDs synthesis have been developed. The main methods involve the Nucleophilic Aromatic Substitution reaction (SNAr) of aryl-substituted 2-bromopyridines (Scheme 1, a).10-11 Ruthenium12 and copper13 catalyzed cyclization have also been developed for the divergent synthesis of aryl-substituted 2-aminopyridines (Scheme 1, b).

Indole, pyrrole and other

heterocycles were used as nucleophiles for the capture of 1,4-oxazepine intermediates leading to Scheme 1. Methods for the construction of 2-amino-4,6-diarylpyridine derivatives


4

Page 5 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ADPDs.14 N-Substituted formamides acting as nucleophiles react with in situ generated 1,4oxazepines from N-propargylic β-enaminones followed by spontaneous N-deformylation to ADPDs15 (Scheme 1, c).14-15 However, these methods for the synthesis of ADPDs usually involve the use of sophisticated ligands that require the use of toxic transition metals as catalysts, which seriously limit their application in biological and medical research. In addition, aliphatic amines are not well tolerated in those amination reactions, the diversity of the target compounds is limited and the structure of the target compounds is largely different from that of the biological molecules (Figure 1 vs. Scheme 1a–1c). Accordingly, it is very desirable and urgent to develop a concise, highly selective method to construct ADPDs. Cyclic 1,1-enediamines are versatile building blocks16-18 widely used in the synthesis of a variety of fused heterocyclic compounds, including various biologically active heterocycles. However, acyclic 1,1-enediamines (EDAMs) have not been considered for many years. Rare studies have shown that EDAMs serve as bis-nucleophiles (α-carbon and N as nucleophilic sites) and react with bis-electrophiles to produce fused heterocyclic compounds.19-20 In continuation of our interest in the synthesis of functionalized heterocyclic compounds with pharmacological activity and from available building blocks, we aim to use EDAMs as building blocks to construct novel 2-amino-4,6-diarylpyridine ring systems (Scheme 1). The use of the N(3) of EDAMs 2 to attack the nucleophilic sites shows little steric effect ((N3) vs. NHAr ''). However, the C(1) instead of the

N(3) of EDAMs 2 can attack the nucleophilic sites C(3) of α,β-

unsaturated ketones 1. Then, the N(3) of EDAMs 2 attacked the nucleophilic sites C(1) of α,βunsaturated ketones 1 (Scheme 1). This reaction through aromatization produced the target ADPDs. There were one C-C bond, one C=N bond and two C=C bonds formed. Notably, when the EDAMS 3 reacted with α,β-unsaturated ketones 1 to produce the ADPDs 6, the reaction


5


Page 6 of 41

occurred through regioselective Michael addition, cyclization and loss of one molecular HNO2. Here, the nitro group of EDAMs acts as activating group (AG) and orienting group (OG), which makes the nucleophilic ability of the α-C more uncommon than that of the N atom. As the reaction proceeds smoothly and produces the intermediate, the nitro group of the intermediate can be easily removed under the appropriate basic conditions (Scheme 1). This protocol demonstrated that the most important feature was the action of the nitro group of the EDAMs as AG and OG, which was used in the synthesis of 2- amino-substituted heterocycles. Using this property, various substituted (for example alkyl, aryl, multi-cyclic substituted and etc.) 2aminoheterocycles

including 2-aminopyridines,

2-amionpyrroles,

2-aminoquinolines,

2-

aminoindoles and others can be easily constructed. 

RESULTS AND DISCUSSION To obtain the 2-amino-4,6-diarylpyridines (ADPDs), we used (E)-chalcone 1a reacted with 2-

amino-1-phenyl-7,8-dihydroquinoline-4,5(1H, 6H)-dione 2a to synthesize the target compound 4a and determine the optimal conditions for this model reaction. First, different types of solvents including ethanol, acetone, 4-dioxane and toluene were evaluated at reflux conditions. Fortunately, the reaction in 1,4-dioxane at reflux can produce the target compound with 40% yield (Table 1, entries 1-4). Then, different promoters including Cs2CO3, Et3N and piperine were combined in this reaction. The results demonstrated that the 1,4-dioxane is an excellent solvent and can produce the target compound in moderate yield (60%) (Table 1, entries 5–8). It showed that the promoter Et3N can promote the reaction and increase the yield from 40 to up to 60% (Table 1, entry 3 vs. 7). Afterwards, piperidine was added to the 1,4-dioxane and refluxed for 9 hours and produced compound 4a in lower yield (56%) (Table 1, entry 13). Then, the inorganic base Cs2CO3 was evaluated as promoter under the same conditions. When the Cs2CO3 is used as


6

Page 7 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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

time/(h)

Yielde (%)

reflux

12

–

−

reflux

12

–

1,4-dioxane

−

reflux

12

40

4

toluene

−

reflux

12

–

5

ethanol

Et3Nb

reflux

9

complex

6

acetone

Et3Nb

reflux

9

complex

7

1,4-dioxane

Et3Nb

reflux

9

8

toluene

Et3Nb

reflux

9

9

1,4-dioxane

Piperidineb

reflux

9

10

ethanol

Cs2CO3b

reflux

9

complex

11

acetone

Cs2CO3b

reflux

9

complex

12

1,4-dioxane

Cs2CO3b

reflux

9

13

toluene

Cs2CO3b

reflux

9

14

1,4-dioxane

t-BuOKb

reflux

9

complex

15

1,4-dioxane

Cs2CO3c

reflux

9

60

16

1,4-dioxane

Cs2CO3d

reflux

9

81

17

1,4-dioxane

Cs2CO3b

reflux

6

75

18

1,4-dioxane

Cs2CO3b

reflux

12

82

entry

solvent

base

1

ethanol

−

2

acetone

3

t (℃)

60 complex 56

83 complex

a

Reagents and conditions: Chalcone 1a (1.0 mmol), EDAMs 2a (1.2 mmol), solvent (10 mL). promoter (1.0 mmol). c promoter (0.5 mmol). d promoter (1.5 mmol). e Isolated yield based on 1a. b


7


Page 8 of 41

promoter in ethanol, or acetone, or toluene at reflux, the reaction is more complex. Only the use of 1,4-dioxane as solvent at reflux promoted by Cs2CO3 is particularly satisfactory and produces compound 4a in good yield (83%) (Table 1, entries 10–13). Then, t-BuOK was used in this reaction and it was found that the reaction was more complex due to the strong alkalinity of tBuOK (Table 1, entries 14). The above findings indicated that the 1,4- dioxane is the optimal solvent and Cs2CO3 is the best promoter. Afterwards, the amount of Cs2CO3 was evaluated and it was determined that the optimal amount is about 1 equiv. (Table 1, entry 12 vs. 15–16). Ultimately, the reaction times were evaluated (Table 1, entries 17–18). We compared the entry 12 and 17–18, and found that the best reaction time was about 9 hours. Therefore, the optimal conditions are 1,4-dioxane at reflux for about 9 hours and promoted by 1.0 equiv. In order to explore the scope and limitations of the cascade reaction, different α,β-unsaturated ketones 1 and 2-amino-1-aryl-7,8-dihydroquinoline-4,5(1H,6H)-diones 2 were used as substrates to construct the 2-amino-4,6-diarylpyridines 4 (Table 2). The results showed that the substituents on α,β-unsaturated ketones 1 had only a slight effect on the yield, and there were not obvious rules. The substituents on 2-amino-1-aryl-7,8-dihydroquinoline-4,5(1H,6H)-diones 2 had an effect on the yield. In general, the electron-withdrawing group (F, Cl) usually is favorable for the yield (Table 2, 4d vs. 4a; 4e vs. 4b; 4i vs. 4f). Overall, all the substrates can be used in the reaction and produce 2-amino-4,6-diarylpyridines 4 in good to excellent yields (Table 2). To further explore the scope and limitations of the cascade reaction, different α,β-unsaturated ketones 1 and EDAMs 3 were used as substrates to construct the 2-amino-4,6-diarylpyridines 5 (Table 3). The results demonstrated that the optimal temperature is about 50 0C and the substituents on α,β-unsaturated ketones 1 and on EDMAs 3 had only a slight effect on the yield. In short, all the substrates on α,β-unsaturated ketones 1 or on EDAMs can be used in the reaction


8

Page 9 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


and produce the target compounds 5 in good to excellent yields (Table 3). Table 2. Synthesis of 2-amino-4,6-diarylpyridine derivatives 4a–4la-b

a

Reagents and conditions: α,β-unsaturated ketones 1 (1.0 mmol), EDAMs 2 (1.2 mmol),Cs2CO3

(1.0 mmol), 1,4-dioxane (10 mL). b Isolated yield based on 1.


9


Page 10 of 41

Table 3. Synthesis of 2-amino-4,6-diarylpyridine derivatives 5


10

Page 11 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


In order to obtain the non-nitro 2-amino-4,6-diarylpyridines, we need to assess the optimal base that can cleave the nitro group from the intermediate compound that forms the target compounds by the cascade reaction of α,β-unsaturated ketones 1 with EDAMs 3. Thus, the mixture of α,β-unsaturated ketones 1 and EDAMs 3 was reacted under various conditions (Table 4, entries 1–14). The results showed that the reaction could not be performed under at room temperature and reflux without adding base promoters (Table 4, entries 1–2). Then, Cs2CO3 was added to the reaction and it was found that Cs2CO3 in 1,4-dioxane particularly favored the production of compounds 5a in good yield (Table 4, entry 3). In addition, the stronger base tBuOK was also used as promoter in this reaction, but it was found to make the reaction more complicated due to excessive alkalinity, and positive results could not be obtained (Table 4, entries 5–6). Subsequently, Et3N (1.0 equiv.) was added to the 1,4-dioxane or toluene solvent. The results showed that Et3N has some effect on the synthesis of the target compound 6a and resulted in a 38% yield (Table 4, entry 7). Then, piperidine was added into each of the various solvents, including acetone, ethanol, 1,4-dioxane and toluene (Table 4, entries 9–12). Fortunately, when piperidine is used as promoter in 1,4-dioxane, the reaction can produce the target compound 6a with a yield of 83% (Table 4, entry 11). Finally, the evaluation of the reaction time showed that the optimal reaction time was about 9 hours (Table 4, entries 13–14). Therefore, the optimal reaction conditions for the synthesis of ADPDs require the mixture to be in 1,4dioxane at reflux for 9 hours promoted by 1.0 equiv. piperidine. To further explore the universality of the cascade reaction. Different α,β-unsaturated ketones 1 with EDAMs 3 were combined in this reaction under the optimal conditions (Table 5, compounds 6a–6p). We eventually successfully synthesized the target compounds 6. The results revealed that the different substituents (H, F, Cl, Me,) at the 4 and 4' positions of α,β-unsaturated ketones 1 have a


11


Page 12 of 41

Table 4. Optimization of conditions for synthesis of 2-amino-4,6-diarylpyridinesa

a

Entry

Solvent

Promoter

T(°C)

Time (H)

5a/Yieldb (%)

6a/ Yieldb (%)

1

1,4-dioxane

−

r.t

12

–

–

2

toluene

−

r.t

12

–

–

3

1,4-dioxane

Cs2CO3

reflux

9

81

–

4

toluene

Cs2CO3

reflux

9

complex

complex

5

1,4-dioxane

t-BuOK

reflux

9

complex

complex

6

toluene

t-BuOK

reflux

9

complex

complex

7

1,4-dioxane

Et3N

reflux

9

40

38

8

toluene

Et3N

reflux

9

complex

complex

9

acetone

piperidine

reflux

9

complex

complex

10

ethanol

piperidine

reflux

9

complex

complex

11

1,4-dioxane

piperidine

reflux

9

–

83

12

toluene

piperidine

reflux

9

complex

complex

13

1,4-dioxane

piperidine

reflux

6

–

80

14

1,4-dioxane

piperidine

reflux

12

–

83

Reagents and conditions: Chalcone 1a (1.0 mmol), EDAMs 3a (1.2 mmol), Base (1.0

mmol), solvent (10 mL). b Isolated yield based on 1a. r.t = room temperature.

slight effect on the yield of compounds 6. In general, the yield of the electron-withdrawing group substituted compound 1 is higher than that of the electron-donating group substituted compound. The same rules applied in the substrate EDAMs 3. In short, we can easily construct the non-nitro


12

Page 13 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


group 2-amino-4,6-diarylpyridines 6 with good to excellent yield that includes a diversity of α,βunsaturated ketones 1 and EDAMs 3. Table 5. Synthesis of 2-amino-4,6-diarylpyridine derivatives 6


13


Page 14 of 41

Products 4–6 were characterized by proton nuclear magnetic resonance (1H NMR), 13C NMR, Infrared (IR) spectroscopy and high resolution mass spectroscopy (HRMS). The characterization results all confirmed the proposed structures. In order to further verify the structure of the 2amino-4,6-diaryl pyridine derivatives, products 4j, 5m and 6j were selected as representative compounds and characterized by X-ray crystallography, as shown in Figure S1−Figure S3 (CCDC 1870261, CCDC 1870252 ＆CCDC 1870253) (Supporting Information). Based on the above experimental results we propose a mechanism as outlined in Scheme 2. First, the α-C of EDAMs 2 acting as the nucleophilic site attack the α,β-unsaturated ketones 1 through the Michael addition promoted by the base to generate the intermediate 8. This is followed by the imine-enamine tautomerization to produce the intermediate 9. Then, the primary amino group of intermediate 9 attacks the carbonyl via intramolecular cyclization reaction to produce intermediate 10. Next, the intermediate loses one molecule of H2O induced by heat to give intermediate 11. The intermediate 11 is oxidized by air to give intermediate 12. Then, intermediate 12 undergoes keto-enol tautomerization and generates intermediate 13. Eventually, intermediate 13 is oxidized by air to produce the target compounds 4 (Scheme 2). The formation of the target compound 5–6 through the proposed mechanism is described in the Supporting Information (Scheme S1). To testify the mechanism of this reaction, (E)-1-(4-chlorophenyl)-3-phenylprop-2-en-1-one (1d), 2-amino-1-(4-chlorophenyl)-7,8-dihydroquinoline-4,5(1H,6H)-dione (2b) and Cs2CO3 were charged in a round-bottom flask. The reaction mixture was under a nitrogen atmosphere for 110°C only for 2 hours. Then, the reaction mixture was injected into the HPLC-HRMS system. The four molecular ion peaks that appeared in the high-resolution mass spectrum were: HRMS (TOF ES+): m/z calcd for C30H25Cl2N2O3 [M+H]+, 531.1237; found, 531.1240; HRMS (TOF


14

Page 15 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ES+): m/z calcd for C30H25Cl2N2O3 [M+H]+, 531.1237; found, 531.1240; HRMS (TOF ES+): m/z calcd for C30H25Cl2N2O3 [M+H]+, 531.1237; found, 531.1233. There are the HRMS spectrum of intermediate 8/9/10 (supporting information, Figure S106−Figure S109); HRMS (TOF ES+): m/z calcd for C30H21Cl2N2O2 [M+H]+, 511.0975; found, 511.0973, which is the HRMS spectra of intermediate 12 or 13) (supporting information, Figure S106 and Figure S110). The pure intermediate 12/13 could not be isolated by silica gel column chromatography under a nitrogen atmosphere. Therefore, we believe that intermediate 12/13 had been oxidized by oxygen when we concentrated the reaction mixture. Based on the results and the relative literature,21 the proposed mechanism of the cascade reaction was describe as Scheme 2. Scheme 2. Proposed Mechanism for the formation of 2-amino-4,6-diarylpyridines



CONCLUSIONS

In this work, we have developed a feasible strategy for the synthesis of novel ADPDs via a basepromoted cascade reaction of α,β-unsaturated ketones 1 with EDAMs 2–3. We use a concise


15


Page 16 of 41

strategy to synthesize three novel types of ADPDs. This reaction provides a novel, rapid, and efficient route for the preparation of a variety of 2-amino-4,6-diarylpyridines in good to excellent yields from readily available building blocks of α,β-unsaturated ketones 1 and EDAMs. Moreover, this procedure indicates that the most important feature in the synthesis of of 2amino-substituted heterocycles was the nitro group of EDAMs serving as AG and OG. Taking advantage of this property, various substituted 2-aminoheterocycles, including 2-aminopyridines, 2-amionpyrroles, 2-aminoquinolines, 2-aminoindoles and others can be easily constructed. The diversity of the target compounds 4–6 increases the chance of identifying drug lead compounds with pharmacological activity in the future. 

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 ppm, and J values are given in Hz, and deuterated DMSO-d6 or CDCl3 was 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. HRMs were performed on a Agilent LC/Msd TOF instrument. X-ray diffraction was obtained by APEX DUO. All chemicals and solvents were used as received without further purification unless otherwise stated. All chemicals were purchased from Adamas-beta. Column chromatography was performed on silica gel (Qingdao, 200–300 mesh). Compounds 1 were prepared according to the literature.22 Compounds 2-3 were prepared according to the literature.23 General procedure for the synthesis of compounds 4. α,β-Unsaturated ketones 1 (1.0 mmol), 1,4-dioxane (10 mL) and EDAMs 2 (1.2 mmol) were added into a 25 mL round bottom flask,


16

Page 17 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


then Cs2CO3 (1.0 mmol) was added to the mixture. The solution was stirred under reflux for 9 hours until thin layer chromatography (TLC) analysis showed complete consumption of the α,βunsaturated ketones 1. Ultimately, 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 separtated by column chromatography (Petro/AcOEt = 50/1) to obtain pure target products 4 with a yield of 83–92%. 6-Hydroxy-2,4,10-triphenylbenzo[b][1,8]naphthyridin-5(10H)-one (4a). Yellow solid; yield: 365 mg, 83%; Mp: 260.8–261.7 °C; IR (KBr): 3443, 3057, 1631, 1582, 1537, 1481, 1259, 748 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 6.20 (d, J = 8.5 Hz, 1H, ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 7.36–7.54 (m, 11H, ArH), 7.73–7.88 (m, 6H, ArH), 13.94 (br, 1H, OH); 13

C{1H}NMR (125 MHz, DMSO-d6): δ = 106.7, 108.3, 110.3, 111.4, 118.1, 127.8, 128.1, 128.1,

128.7, 129.3, 130.1, 130.6, 131.3, 136.4, 137.1, 139.7, 141.0, 143.8, 152.9, 154.2, 158.6, 162.9, 183.0. HRMS (TOF ES+): m/z calcd. for C30H21N2O2 [M+H]+, 441.1598; found, 441.1602. 10-(4-Chlorophenyl)-6-hydroxy-2,4-diphenylbenzo[b][1,8]naphthyridin-5(10H)-one

(4b).

Yellow solid; yield: 403 mg, 85%; Mp: 288.3–289.2 °C; IR (KBr): 3442, 1606, 1587, 1535, 1483, 1261, 1175, 744 cm-1; 1H NMR (500 MHz, DMSO-d6 + CDCl3): δ = 6.23 (d, J = 8.5 Hz, 1H, ArH), 6.62 (d, J = 8.0 Hz, 1H, ArH), 7.38–7.52 (m, 11H, ArH), 7.61 (s, 1H, ArH), 7.75– 7.85 (m, 4H, ArH), 13.83 (br, 1H, OH); 13C{1H}NMR (125 MHz, DMSO-d6 + CDCl3): δ = 106.4, 108.5, 110.3, 111.5, 118.2, 127.7, 127.9, 128.5, 129.1, 130.5, 131.0, 131.8, 134.1, 136.1, 137.2, 138.4, 140.9, 143.5, 152.8, 154.2, 158.8, 163.0, 182.9. HRMS (TOF ES+): m/z calcd. for C30H20ClN2O2 [M+H]+, 475.1208; found, 475.1208. 6-Hydroxy-10-(4-methoxyphenyl)-2,4-diphenylbenzo[b][1,8]naphthyridin-5(10H)-one

(4c).

Yellow solid; yield: 394 mg, 84%; Mp: 290.6–291.7 °C; IR (KBr): 3415, 1631, 1539, 1481,


17


Page 18 of 41

1246, 1173, 788, 750 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 3.92 (s, 3H, OCH3), 6.24 (d, J = 8.5 Hz, 1H, ArH), 6.63 (d, J = 8.0 Hz, 1H, ArH), 7.25–7.28 (m, 2H, ArH), 7.41–7.51 (m, 11H, ArH), 7.68 (s, 1H, ArH), 7.93 (d, J = 7.0 Hz, 2H, ArH), 13.95 (br, 1H, OH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 56.0, 106.9, 108.2, 110.3, 111.4, 115.7, 118.2, 127.9, 128.1, 128.7, 129.3, 131.1, 131.3, 132.2, 136.3, 137.2, 141.0, 144.2, 153.1, 154.2, 158.7, 159.6, 162.8, 183.0. HRMS (TOF ES+): m/z calcd. for C31H23N2O3 [M+H]+, 471.1703; found, 471.1703. 2-(4-Fluorophenyl)-6-hydroxy-4,10-diphenylbenzo[b][1,8]naphthyridin-5(10H)-one

(4d).

Yellow solid; yield: 384 mg, 84%; Mp: 270.5–271.4 °C; IR (KBr): 3444, 1604, 1585, 1479, 1399, 1259, 1161, 750 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 6.19 (d, J = 9.0 Hz, 1H, ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 7.19–7.23 (m, 2H, ArH), 7.47–7.53 (m, 8H, ArH), 7.68–7.76 (m, 4H, ArH), 7.91–7.96 (m, 2H, ArH), 13.92 (br, 1H, OH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 106.7, 108.3, 110.3, 111.3, 116.2 (d, J = 21.3 Hz), 118.0, 128.1, 128.1, 128.7, 129.3, 130.0, 130.2, 136.6, 133.7, 136.4, 139.7, 140.9, 143.8, 152.8, 154.3, 157.5, 162.9, 164.3 (d, J = 247.5 Hz), 183.0. HRMS (TOF ES+): m/z calcd. for C30H20FN2O2 [M+H]+, 459.1503; found, 459.1504. 10-(4-Chlorophenyl)-2-(4-fluorophenyl)-6-hydroxy-4-phenylbenzo[b][1,8]naphthyridin-5(10H)-one (4e). Yellow solid; yield: 442 mg, 90%; Mp: 278.6–279.5 °C; IR (KBr): 3452, 1605, 1587, 1539, 1484, 1263, 1156, 840 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 6.19 (d, J = 8.5 Hz, 1H, ArH), 6.65 (d, J = 8.0 Hz, 1H, ArH), 7.26 (t, J = 8.8 Hz, 2H, ArH), 7.47–7.52 (m, 6, ArH), 7.58–7.62 (m, 2H, ArH), 7.71 (s, 1H, ArH), 7.81 (d, J = 8.5 Hz, 2H, ArH), 7.95–7.99 (m, 2H, ArH), 13.88 (br, 1H, OH);

13

C{1H}NMR (125 MHz, DMSO-d6): δ = 106.7, 108.5, 110.3,

111.4, 116.3 (d, J = 21.3 Hz), 118.2, 128.1, 128.2, 128.7, 130.3, 130.7, 132.1, 133.7, 133.9, 136.5, 138.6, 140.8, 143.6, 152.8, 154.3, 157.7, 162.8, 164.3 (d, J = 248.0 Hz), 183.0. HRMS (TOF ES+): m/z calcd. for C30H19ClFN2O2 [M+H]+, 493.1114; found, 493.1117.


18

Page 19 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2-(4-Fluorophenyl)-6-hydroxy-10-(4-methoxyphenyl)-4-henylbenzo[b][1,8]naphthyridin-5(10 -H)-one (4f). Yellow solid; yield: 434 mg, 89%; Mp: 241.8–242.7 °C; IR (KBr): 3441, 1600, 1539, 1510, 1479, 1246, 1170, 841 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 3.93 (s, 1H, OCH3), 6.24 (d, J = 8.5 Hz, 1H, ArH), 6.63 (d, J = 8.0 Hz, 1H, ArH), 7.24–7.27 (m, 4H, ArH), 7.43–7.51 (m, 8H, ArH), 7.70 (s, 1H, ArH), 7.97–8.01 (m, 2H, ArH), 13.93 (br, 1H, OH); 13

C{1H}NMR (150 MHz, CDCl3): δ = 50.9, 101.7, 103.9, 105.9, 106.9, 110.5, 112.7, 123.2,

123.2, 124.0, 124.3, 125.8, 127.4, 130.7, 131.1, 132.1, 136.1, 139.2, 148.3, 149.7, 152.7, 154.8, 158.4, 178.1. HRMS (TOF ES+): m/z calcd. for C31H22FN2O3 [M+H]+, 489.1609; found, 489.1611. 2,4-Bis(4-fluorophenyl)-6-hydroxy-10-phenylbenzo[b][1,8]naphthyridin-5(10H)-one

(4g).

Yellow solid; yield: 409 mg, 86%; Mp: 253.1–254.0 °C; IR (KBr): 3441, 1637, 1590, 1538, 1485, 1265, 1235, 829 cm-1; 19F NMR (470 MHz, DMSO-d6): δ = -114.8, -109.8; 1H NMR (500 MHz, DMSO-d6): δ = 6.19 (d, J = 8.5 Hz, 1H, ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 7.21–7.32 (m, 4H, ArH), 7.49–7.57 (m, 5H, ArH), 7.67–7.76 (m, 4H, ArH), 7.92–7.96 (m, 2H, ArH), 13.91 (br, 1H, OH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 106.7, 108.4, 110.3, 111.3, 114.9 (d, J = 21.3 Hz), 116.3 (d, J = 21.3 Hz), 118.1, 129.4, 130.0, 130.3, 130.6, 131.0, 133.6, 136.5, 137.1, 139.6, 143.8, 152.8, 153.2, 157.6, 162.4 (d, J = 243.8 Hz), 162.9, 164.4 (d, J = 235.0 Hz), 183.0. HRMS (TOF ES+): m/z calcd. for C30H19F2N2O2 [M+H]+, 477.1409; found, 477.1410. 10-(4-Chlorophenyl)-2,4-bis(4-fluorophenyl)-6-hydroxybenzo[b][1,8]naphthyridin-5(10H)one (4h). Yellow solid; yield: 453 mg, 89%; Mp: 287.4–288.3 °C; IR (KBr): 3441, 1602, 1589, 1510, 1484, 1262, 1232, 832 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 6.20 (d, J = 8.3 Hz, 1H, ArH), 6.67 (d, J = 7.7 Hz, 1H, ArH), 7.27–7.33 (m, 4H, ArH), 7.53–7.60 (m, 5H, ArH), 7.74 (s, 1H, ArH), 7.82 (d, J = 7.8 Hz, 2H, ArH), 7.95–7.99 (m, 2H, ArH), 13.87 (br, 1H, OH);


19


Page 20 of 41

13

C{1H}NMR (150 Hz, DMSO-d6): δ = 106.7, 108.6, 110.3, 111.4, 115.0 (d, J = 21.0 Hz), 116.4

(d, J = 21.0 Hz), 118.3, 130.3, 130.7, 130.9, 132.1, 133.6, 133.9, 136.6, 137.0, 138.6, 143.6, 152.8, 153.3, 157.7, 162.5 (d, J = 243.0 Hz), 164.4 (d, J = 256.5 Hz), 183.1. HRMS (TOF ES+): m/z calcd. for C30H18F2ClN2O2 [M+H]+, 511.1019; found, 511.1022. 2,4-Bis(4-fluorophenyl)-6-hydroxy-10-(4-methoxyphenyl)benzo[b][1,8]naphthyridin-5(10H)one (4i). Yellow solid; yield: 465 mg, 92%; Mp: 280.3–281.2 °C; IR (KBr): 3442, 2965, 1599, 1540, 1511, 1246, 1170, 838 cm-1; 19F NMR (470 MHz, DMSO-d6): δ = -114.8, -109.9; 1H NMR (500 MHz, DMSO-d6): δ = 3.92 (s, 3H, OCH3), 6.24 (d, J = 8.5 Hz, 1H, ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 7.25–7.71 (m, 11H, ArH), 7.72 (s, 1H, ArH), 7.98–8.01 (m, 2H, ArH), 13.92 (br, 1H, OH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 56.0, 106.9, 108.3, 110.3, 111.4, 114.9 (d, J = 21.3 Hz), 115.7, 116.3 (d, J = 21.3 Hz), 118.1, 130.3, 130.9, 131.0, 132.1, 133.7, 136.4, 137.1, 144.2, 153.1, 153.2, 158.7 (d, J = 243.8 Hz), 161.5, 162.8, 163.3, 164.4 (d, J = 236.3 Hz), 183.0. HRMS (TOF ES+): m/z calcd. for C31H21F2N2O3 [M+H]+, 507.1515; found, 507.1516. 2-(4-Chlorophenyl)-6-hydroxy-4,10-diphenylbenzo[b][1,8]naphthyridin-5(10H)-one

(4j).

Yellow solid; yield: 403 mg, 85%; Mp: 267.0–267.9 °C; IR (KBr): 3441, 1629, 1586, 1537, 1478, 1258, 1167, 821 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 6.19 (d, J = 8.5 Hz, 1H, ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 7.42–7.88 (m, 16H, ArH), 13.89 (br, 1H, OH);

13

C{1H}NMR

(125 MHz, DMSO-d6): δ = 106.7, 108.4, 110.3, 111.6, 118.1, 128.1, 128.2, 128.7, 129.3, 129.5, 130.0, 130.6, 136.0, 136.3, 136.5, 139.6, 140.8, 143.8, 152.8, 154.4, 157.4, 162.9, 183.0. HRMS (TOF ES+): m/z calcd. for C30H20ClN2O2 [M+H]+, 475.1208; found, 475.1209. 2,10-Bis(4-chlorophenyl)-6-hydroxy-4-phenylbenzo[b][1,8]naphthyridin-5(10H)-one

(4k).

Yellow solid; yield: 447 mg, 88%; Mp: 281.5–282.4 °C; IR (KBr): 3441, 1605, 1585, 1535, 1483, 1261, 1172, 779 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 6.20 (d, J = 8.5 Hz, 1H, ArH),


20

Page 21 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


6.66 (d, J = 8.0 Hz, 1H, ArH), 7.47–7.54 (m, 8H, ArH), 7.60 (d, J = 8.5 Hz, 2H, ArH), 7.72 (s, 1H, ArH), 7.81 (d, J = 8.5 Hz, 2H, ArH), 7.91 (d, J = 8.5 Hz, 2H, ArH), 13.86 (br, 1H, OH); 13

C{1H}NMR (125 MHz, DMSO-d6): δ = 106.7, 108.5, 110.3, 111.7, 118.3, 127.8, 128.1, 128.2,

128.7, 129.4, 129.6, 130.7, 132.1, 133.9, 136.0, 136.3, 136.6, 138.6, 140.7, 143.6, 152.8, 154.4, 157.5, 162.9, 183.1. HRMS (TOF ES+): m/z calcd. for C30H19Cl2N2O2 [M+H]+, 509.0818; found, 509.0822. 2-(4-Chlorophenyl)-6-hydroxy-10-(4-methoxyphenyl)-4-phenylbenzo[b][1,8]naphthyridin-5(10H)-one (4l). Yellow solid; yield: 453 mg, 90%; Mp: 264.6–265.5 °C; IR (KBr): 3432, 1610, 1456, 1401, 1234, 1156, 1078, 776 cm-1; 1H NMR (500 MHz, DMSO-d6 + CDCl3): δ = 3.94 (s, 3H, OCH3), 6.27 (d, J = 8.5 Hz, 1H, ArH), 6.60 (d, J = 8.0 Hz, 1H, ArH), 7.24 (d, J = 8.5 Hz, 3H, ArH), 7.37–7.47 (m, 11H, ArH), 7.64 (s, 1H, ArH), 7.90 (d, J = 8.5 Hz, 2H, ArH), 13.86 (br, 1H, OH);

13

C{1H}NMR (125 MHz, DMSO-d6 + CDCl3): δ = 55.9, 106.7, 108.2, 110.4, 111.6,

115.6, 118.0, 127.9, 128.0, 128.5, 129.2, 129.4, 130.8, 132.0, 136.0, 136.3, 140.9, 144.1, 153.0, 154.3, 157.5, 159.6, 162.9, 182.9. HRMS (TOF ES+): m/z calcd. for C31H22ClN2O3 [([M+H]+, 505.1313; found, 505.1318. General procedure for the synthesis of compounds 5–6. α,β-Unsaturated ketones 1 (1.0 mmol), 1,4-dioxane (10 mL) and EDAMs 3 (1.2 mmol) were added into a 25 mL round bottom flask, then Cs2CO3 or piperidine (1.0 mmol) was added to the mixture. The solution was stirred at heating condition for 9 hours until thin layer chromatography (TLC) analysis showed complete consumption of the α,β-unsaturated ketones 1. Ultimately, 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 separtated by column chromatography (Petro/AcOEt = 50/1) to obtain pure target products 5–6 with a yield of 80–95%.


21


Page 22 of 41

N-Benzyl-3-nitro-4,6-diphenylpyridin-2-amine (5a). Yellow solid; yield: 233 mg, 83%; Mp: 91.0–92.0 °C; IR (KBr): 3404, 3028, 2917, 1591, 1552, 1490, 1241, 776 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 4.78 (d, J = 5.5 Hz, 2H, NCH2), 7.20–7.24 (m, 2H, ArH), 7.31–7.34 (m, 2H, ArH), 7.42–7.49 (m, 10H, ArH), 8.05–8.07 (m, 2H, ArH ), 8.12 (br, 1H, NH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 44.9, 111.0, 127.1, 127.7, 127.7, 127.8, 128.7, 129.3, 129.1, 129.2, 129.3, 129.5, 130.7, 137.1, 137.7, 140.6, 147.0, 150.6, 157.6. HRMS (TOF ES+): m/z calcd. for C24H20N3O2 [M+H]+, 382.1550; found, 382.1550. 3-Nitro-N-phenethyl-4,6-diphenylpyridin-2-amine (5b). Yellow solid; yield: 331 mg, 84%; Mp: 109.9–110.9 °C; IR (KBr): 3414, 3025, 2933, 1594, 1579, 1557, 1256, 727 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.99 (t, J = 7.3 Hz, 2H, CH2), 3.79–3.84 (m, 2H, NCH2), 7.21–7.53 (m, 14H, ArH), 7.62 (br, 1H, NH), 8.20 (d, J = 6.5 Hz, 2H, ArH); 13C{1H}NMR (125 MHz, DMSOd6): δ = 35.5, 43.3, 110.9, 126.6, 127.7, 127.8, 128.9, 129.0, 129.2, 129.2, 129.3, 129.4, 130.8, 137.3, 137.8, 140.1, 147.3, 150.8, 157.9. HRMS (TOF ES+): m/z calcd. for C25H22N3O2 [M+H]+, 396.1707; found, 396.1707. N-(4-Fluorobenzyl)-3-nitro-4,6-diphenylpyridin-2-amine (5c). Yellow solid; yield: 335 mg, 84%; Mp: 111.7–112.6 °C; IR (KBr): 3418, 2927, 1592, 1579, 1552, 1366, 1219, 761 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 4.77 (d, J = 5.8 Hz, 2H, NCH2), 7.14–7.17 (m, 2H, ArH), 7.21 (s, 1H, ArH), 7.42–7.44 (m, 2H, ArH), 7.47–7.50 (m, 8H, ArH), 8.06–8.08 (m, 2H, ArH), 8.14 (br, 1H, NH);

13

C{1H}NMR (150 MHz, DMSO-d6): δ = 44.2, 111.0, 115.4 (d, J = 21.0 Hz),

127.7, 127.8, 129.2, 129.3, 129.3, 129.5, 129.6, 129.7, 130.7, 136.8, 137.1, 137.7, 147.0, 150.5, 157.6, 161.6 (d, J = 240.0 Hz). HRMS (TOF ES+): m/z calcd. for C24H18FN3O2 [M+H]+, 400.1456; found, 400.1456. N-(4-Chlorophenethyl)-3-nitro-4,6-diphenylpyridin-2-amine (5d). Yellow solid; yield: 364 mg,


22

Page 23 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


85%; Mp: 139.0–140.0 °C; IR (KBr): 3401, 2925, 1591, 1552, 1495, 1358, 1243, 771 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 2.97–3.00 (m, 2H, CH2), 3.79–3.83 (m, 2H, NCH2), 7.21 (br, 1H, NH), 7.30–7.35 (m, 2H, ArH), 7.34–7.39 (m, 2H, ArH), 7.40–7.44 (m, 2H, ArH), 7.46–7.51 (m, 3H, ArH), 7.51–7.55 (m, 3H, ArH), 7.57–7.63 (m, 1H, ArH), 8.14–8.19 (m, 2H, ArH); 13

C{1H}NMR (150 MHz, DMSO-d6): δ = 34.7, 43.0, 110.9, 127.7, 127.8, 128.8, 129.1, 129.2,

129.3, 129.4, 130.8, 131.1, 131.3, 137.3, 137.8, 139.1, 147.3, 150.8, 157.8. HRMS (TOF ES+): m/z calcd. for C25H21ClN3O2 [M+H]+, 430.1317; found, 430.1317. (N-(4-Chlorobenzyl)-3-nitro-4,6-diphenylpyridin-2-amine (5e). Yellow solid; yield: 373 mg, 90%; Mp: 109.2–110.1 °C; IR (KBr): 3388, 2871, 1603, 1522, 1508, 1358, 1253, 700 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 4.77 (d, J = 6.0 Hz, 2H, NCH2), 7.21 (s, 1H, ArH), 7.38–7.51 (m, 12H, ArH), 8.03–8.06 (m, 2H, ArH), 8.15 (br, 1H, NH);

13

C{1H}NMR (125 MHz, DMSO-

d6): δ = 44.3, 111.1, 127.7, 127.8, 128.6, 129.0, 129.2, 129.3, 129.3, 129.5, 130.7, 131.6, 137.1, 137.6, 139.8, 147.0, 150.4, 157.5. HRMS (TOF ES+): m/z calcd. for C24H19ClN3O2 [M+H]+, 416.1160; found, 416.1160. N-(4-Methylbenzyl)-3-nitro-4,6-diphenylpyridin-2-amine (5f). Yellow solid; yield: 351 mg, 89%; Mp: 128.4–129.3 °C; IR (KBr): 3426, 2932, 1609, 1553, 1498, 1368, 1260, 774 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.28 (s, 3H, CH3), 4.78 (d, J = 6.0 Hz, 2H, NCH2), 7.15 (d, J = 8.0 Hz, 2H, ArH), 7.21 (s, 1H, ArH), 7.35 (d, J = 8.0 Hz, 2H, ArH), 7.44–7.47 (m, 2H, ArH), 8.08–8.12 (m, 3H, ArH and NH);

13

C{1H}NMR (125 MHz, DMSO-d6): δ = 21.1, 44.6, 110.9,

127.7, 127.8, 129.2, 129.2, 129.3, 129.4, 130.7, 136.2, 137.2, 137.5, 137.7, 147.1, 150.6, 157.6. HRMS (TOF ES+): m/z calcd. for C25H22N3O2 [M+H]+, 396.1707; found, 396.1707. N-(4-methoxyphenethyl)-3-nitro-4,6-diphenylpyridin-2-amine (5g). Yellow solid; yield: 361mg, 85%; Mp: 124.0–124.9 °C; IR (KBr): 3428, 2831, 1604, 1554, 1510, 1243, 1043, 757 cm-1; 1H


23


Page 24 of 41

NMR (500 MHz, DMSO-d6): δ = 2.92 (t, J = 7.5 Hz, 2H, CH2), 3.73 (s, 3H, ArCH3), 3.75–3.80 (m, 2H, NCH2), 6.89 (d, J = 8.5 Hz, 2H, ArH), 7.19–7.23 (m, 3H, ArH), 7.41–7.43 (m, 2H, ArH), 7.46–7.54 (m, 6H, ArH), 7.59 (br, 1H, NH), 8.17–8.21 (m, 2H, ArH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 34.6, 43.5, 55.5, 110.9, 114.4, 127.7, 127.8, 129.1, 129.2, 129.2, 130.1, 130.8, 131.9, 137.4, 137.8, 147.4, 150.9, 157.9, 158.2. HRMS (TOF ES+): m/z calcd. for C26H24N3O3 [M+H]+, 426.1812; found, 426.1813. N-Benzyl-6-(4-fluorophenyl)-3-nitro-4-phenylpyridin-2-amine (5h). Yellow solid; yield: 351 mg, 88%; Mp: 148.8–149.7 °C; IR (KBr): 3416, 2922, 1606, 1583, 1552, 1242, 836 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 4.78 (d, J = 5.8 Hz, 2H, NCH2), 7.20–7.23 (m, 2H, ArH), 7.25–7.30 (m, 2H, ArH), 7.31–7.34 (m, 2H, ArH), 7.41–7.45 (m, 4H, ArH), 7.46–7.50 (m, 3H, ArH), 8.11–8.16 (m, 3H, ArH and NH);

13

C{1H}NMR (150 MHz, DMSO-d6): δ = 44.9, 111.1,

116.1 (d, J = 21.0 Hz), 127.1, 127.7, 127.7, 128.7, 129.2, 129.3, 129.4, 130.2 (d, J = 9.0 Hz), 134.2, 137.1, 140.6, 147.1, 150.6, 156.5, 164.0 (d, J = 246.0 Hz). HRMS (TOF ES+): m/z calcd. for C24H19FN3O2 [M+H]+, 400.1456; found, 400.1456. 6-(4-Fluorophenyl)-3-nitro-N-phenethyl-4-phenylpyridin-2-amine (5i). Yellow solid; yield: 367 mg, 89%; Mp: 127.6–128.5 °C; IR (KBr): 3414, 2926, 1601, 1586, 1359, 1231, 1163, 853 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 2.94–3.00 (m, 2H, CH2), 3.79–3.82 (m, 2H, NCH2), 7.19–7.24 (m, 2H, ArH), 7.30–7.37 (m, 6H, ArH), 7.41–7.42 (m, 2H, ArH), 7.45–7.49 (m, 3H, ArH), 7.62 (br, 1H, NH), 8.24–8.28 (m, 2H, ArH);

13

C{1H}NMR (150 MHz, DMSO-d6): δ =

35.5, 43.3, 110.7, 116.2 (d, J = 21.0 Hz), 126.6, 127.7, 128.9, 129.1, 129.2, 129.2, 129.3, 130.2 (d, J = 9.0 Hz), 134.3, 137.3, 140.0, 147.4, 150.8, 156.9, 164.1 (d, J = 246.0 Hz). HRMS (TOF ES+): m/z calcd. for C25H21FN3O2 [M+H]+, 414.1612; found, 414.1613. 4-Fluoro-N-(4-fluorobenzyl)-4'-nitro-[1,1':3',1''-terphenyl]-5'-amine (5j). Yellow solid; yield:


24

Page 25 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


358 mg, 86%; Mp: 158.5–159.4 °C; IR (KBr): 3390, 1606, 1585, 1554, 1510, 1352, 1159, 838 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 4.72–4.77 (m, 2H, NCH2), 7.11–7.18 (m, 2H, ArH), 7.21 (br, 1H, NH), 7.26–7.32 (m, 2H, ArH), 7.40–7.45 (m, 2H, ArH),7.46–7.49 (m, 5H, ArH), 8.11–8.15 (m, 3H, ArH);

13

C{1H}NMR (150 MHz, DMSO-d6): δ = 44.2, 110.9, 115.4 (d, J =

22.4 Hz), 116.1 (d, J = 21.0 Hz), 127.7, 129.2, 129.4, 129.5, 129.6, 129.7, 130.2 (d, J = 9.0 Hz), 134.2, 136.8, 136.8, 137.0, 147.1, 150.4, 156.4, 161.6 (d, J = 240.0 Hz), 164.0 (d, J = 247.5 Hz). HRMS (TOF ES+): m/z calcd. for C24H18F2N3O2 [M+H]+, 418.1362; found, 418.1360. N-(4-Chlorobenzyl)-6-(4-fluorophenyl)-3-nitro-4-phenylpyridin-2-amine (5k). Yellow solid; yield: 381 mg, 88%; Mp: 118.9–119.8 °C; IR (KBr): 3398, 1600, 1557, 1494, 1298, 1165, 1017, 687 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 4.75 (d, J = 6.0 Hz, 2H, NCH2), 7.22–7.39 (m, 2H, ArH), 7.38–7.49 (m, 9H, ArH), 8.11–8.15 (m, 3H, ArH); 13C{1H}NMR (125 MHz, DMSOd6): δ = 44.3, 110.9, 116.1 (d, J = 21.3 Hz), 127.7, 128.7, 129.3, 129.4, 129.5, 130.1, 130.2, 131.6, 134.1, 137.0, 139.7, 147.1, 150.4, 156.4, 164.0 (d, J = 247.5 Hz). HRMS (TOF ES+): m/z calcd. for C24H18ClFN3O2 [M+H]+, 434.1066; found, 434.1067. (4-Chlorophenethyl)-6-(4-fluorophenyl)-3-nitro-4-phenylpyridin-2-amine (5l). Yellow solid; yield: 402 mg, 90%; Mp: 151.9–152.8 °C; IR (KBr): 3406, 2918, 1604, 1582, 1553, 1490, 1200, 838 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 2.97 (t, J = 7.3 Hz, 2H, CH2), 3.76–3.82 (m, 2H, NCH2), 7.19–7.23 (m, 1H, ArH), 7.28–7.33 (m, 2H, ArH), 7.34–7.37 (m, 4H, ArH), 7.41–7.42 (m, 2H, ArH), 7.44–7.50 (m, 3H, ArH), 7.60 (br, 1H,

NH), 8.22–8.26 (m, 3H, ArH);

13

C{1H}NMR (150 MHz, DMSO-d6): δ = 34.7, 43.0, 110.7, 116.2 (d, J = 21.0 Hz), 127.7, 128.8,

129.2, 129.3, 130.2, 130.2, 131.1, 131.3, 134.3, 137.2, 139.1, 147.3, 150.8, 156.7, 164.1 (d, J = 243.0 Hz). HRMS (TOF ES+): m/z calcd. for C25H20ClFN3O2 [M+H]+, 448.1223; found, 448.1225.


25


Page 26 of 41

6-(4-Fluorophenyl)-N-(4-methylbenzyl)-3-nitro-4-phenylpyridin-2-amine (5m). Yellow solid; yield: yield: 380 mg, 92%; Mp: 144.0–144.9 °C; IR (KBr): 3414, 2933, 1606, 1553, 1509, 1250, 1157, 854 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.29 (s, 3H, CH3), 4.77 (d, J = 6.0 Hz, 2H, NCH2), 7.16 (d, J = 8.0 Hz, 2H, ArH), 7.23 (s, 1H, ArH), 7.28–7.38 (m, 4H, ArH), 7.44–7.46 (m, 2H, ArH), 7.48–7.53 (m, 3H, ArH), 8.09 (m, 1H, NH), 8.18–8.21 (m, 2H, ArH);

13

C{1H}NMR

(125 MHz, DMSO-d6): δ = 21.1, 44.7, 110.7, 116.1 (d, J = 21.3 Hz), 127.7, 127.8, 129.2, 129.3, 129.4, 130.1, 130.2, 134.2, 136.2, 137.1, 137.5, 147.1, 150.5, 156.5, 164.0 (d, J = 247.5 Hz). HRMS (TOF ES+): m/z calcd. for C25H21FN3O2 [(M+H)+], 414.1612; found, 414.1612. 6-(4-Fluorophenyl)-N-(4-methoxyphenethyl)-3-nitro-4-phenylpyridin-2-amine (5n). Yellow solid; yield: 372 mg, 84%; Mp: 159.5–160.4 °C; IR (KBr): 3419, 2937, 1606, 1552, 1491, 1243, 1158, 854 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.91 (t, J = 7.3 Hz, 2H, CH2), 3.73 (s, 3H, OCH3), 3.72–3.78 (m, 2H, NCH2), 6.86–6.92 (m, 2H, ArH), 7.18–7.23 (m, 3H, ArH), 7.35 (t, J = 8.8 Hz, 2H, ArH), 7.40–7.42 (m, 2H, ArH), 7.45–7.50 (m, 3H, ArH), 7.59 (br, 1H, NH), 8.23– 8.28 (m, 2H, ArH);

13

C{1H}NMR (125 MHz, DMSO-d6): δ = 34.6, 43.5, 55.5, 110.8, 114.4,

116.1 (d, J = 21.3 Hz), 127.7, 129.0, 129.2, 129.2, 130.2 (d, J = 12.5 Hz), 131.9, 134.3, 134.3, 137.3, 147.5, 150.9, 156.8, 158.2, 164.1 (d, J = 246.3 Hz). HRMS (TOF ES+): m/z calcd. for C26H23FN3O3 [M+H]+, 444.1718; found, 444.1718. 4,6-Bis(4-fluorophenyl)-3-nitro-N-phenethylpyridin-2-amine (5o). Yellow solid; yield: 362 mg, 84%; Mp: 155.0–155.9 °C; IR (KBr): 3418, 2932, 1602, 1553, 1503, 1441, 1238, 835 cm-1; 19F NMR (470 MHz, DMSO-d6): δ = -113.0, -110.8; 1H NMR (500 MHz, DMSO-d6): δ = 2.98 (t, J = 7.5 Hz, 2H, CH2), 3.78–3.84 (m, 2H, NCH2), 7.21–7.24 (m, 2H, ArH), 7.29–7.37 (m, 8H, ArH), 7.46–7.49 (m, 2H, ArH), 7.68 (m, 1H, NH), 8.25–8.27 (m, 2H, ArH and NH); 13

C{1H}NMR (125 MHz, DMSO-d6): δ = 35.5, 43.3, 110.8, 116.1 (d, J = 21.3 Hz), 126.6, 128.9,


26

Page 27 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


129.2, 130.0, 130.0, 130.2, 130.3, 133.7, 134.2, 140.0, 146.6, 151.0, 156.9, 162.9 (d, J = 245.0 Hz), 164.1 (d, J = 246.3 Hz). HRMS (TOF ES+): m/z calcd. for C25H20F2N3O2 [M+H]+, 432.1518; found, 432.1518. N-(4-Chlorobenzyl)-4,6-bis(4-fluorophenyl)-3-nitropyridin-2-amine (5p). Yellow solid; yield: 388 mg, 86%; Mp: 156.3–157.2 °C; IR (KBr): 3411, 2928, 1605, 1553, 1505, 1230, 1160, 828 cm-1; 19F NMR (565 MHz, DMSO-d6): δ = -112.8, -110.9; 1H NMR (600 MHz, DMSO-d6): δ = 4.76 (d, J = 5.9 Hz, 2H, NCH2), 7.23 (s, 1H, ArH), 7.28–7.34 (m, 4H, ArH), 7.35–7.41 (m, 2H, ArH), 7.44–7.48 (m, 2H, ArH), 7.47–7.50 (m, 2H, ArH), 8.11–8.14 (m, 2H, ArH), 8.21 (br, 1H, NH); 13C{1H}NMR (150 MHz, DMSO-d6): δ = 44.3, 111.0, 116.1 (d, J = 21.0 Hz), 116.2 (d, J = 21.0 Hz), 128.7, 129.4, 129.5, 130.1 (d, J = 9.0 Hz), 130.2 (d, J = 7.5 Hz), 131.6, 133.4, 134.1, 139.7, 146.2, 150.5, 156.5, 162.9 (d, J = 244.5 Hz), 164.0 (d, J = 246.0 Hz). HRMS (TOF ES+): m/z calcd. for C24H17ClF2N3O2 [M+H]+, 452.0972; found, 452.0973. 4,6-Bis(4-fluorophenyl)-N-(4-methoxyphenethyl)-3-nitropyridin-2-amine (5q). Yellow solid; yield: 391 mg, 85%; Mp: 142.9–143.8 °C; IR (KBr): 3427, 2932, 1604, 1584, 1356, 1250, 1162, 829 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.91 (t, J = 7.3 Hz, 2H, CH2), 3.73 (s, 3H, OCH3), 3.72–3.79 (m, 2H, NCH2), 6.88–7.00 (m, 2H, ArH), 7.21–7.49 (m, 9H, ArH), 7.66 (br, 1H, NH), 8.24–8.28 (m, 2H, ArH);

113

C{1H}NMR (125 MHz, DMSO-d6): δ = 34.5, 43.5, 55.5, 110.8,

114.4, 116.1 (d, J = 22.5 Hz), 116.2 (d, J = 21.3 Hz), 128.8, 130.1 (d, J = 11.3 Hz), 130.2 (d, J = 8.8 Hz), 131.8, 131.9, 133.7, 133.8, 134.2, 146.6, 151.0, 156.9, 158.2, 162.9 (d, J = 243.8 Hz), 164.1 (d, J = 246.3 Hz). HRMS (TOF ES+): m/z calcd. for C26H22F2N3O3 [M+H]+, 462.1624; found, 462.1625. 6-(4-Chlorophenyl)-3-nitro-N,4-diphenylpyridin-2-amine (5r). Yellow solid; yield: 377 mg, 94%; Mp: 149.5–150.4 °C; IR (KBr): 3367, 1596, 1554, 1450, 1315, 1255, 1093, 830 cm-1; 1H


27


Page 28 of 41

NMR (600 MHz, DMSO-d6): δ = 7.11 (br, 1H, NH), 7.38–7.56 (m, 10H, ArH), 7.65 (d, J = 7.8 Hz, 2H, ArH), 8.12 (d, J = 8.6 Hz, 2H, ArH), 9.11 (s, 1H, ArH);

13

C{1H}NMR (150 MHz,

DMSO-d6): δ = 113.2, 122.3, 123.7, 127.8, 128.9, 129.3, 129.4, 129.4, 129.5, 131.7, 135.7, 136.2, 136.4, 139.8, 146.6, 147.7, 155.5. HRMS (TOF ES+): m/z calcd. for C23H17ClN3O2 [M+H]+, 402.1004; found, 402.1004. N-(4-Chlorobenzyl)-6-(4-chlorophenyl)-3-nitro-4-phenylpyridin-2-amine (5s). Yellow solid; yield: 426 mg, 95%; Mp: 119.7–120.6 °C; IR (KBr): 3420, 2934, 1599, 1553, 1511, 1242, 1109, 835 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 4.75 (d, J = 5.8 Hz, 2H, NCH2), 7.23 (s, 1H, ArH), 7.39 (d, J = 8.4 Hz, 2H, ArH), 7.42–7.52 (m, 9H, ArH), 8.06–8.09 (m, 2H, ArH), 8.16 (br, 1H, NH);

13

C{1H}NMR (150 MHz, DMSO-d6): δ = 44.4, 111.1, 127.7, 128.7, 128.0, 129.2,

129.3, 129.4, 129.5, 129.6, 129.8, 131.7, 135.6, 136.4, 136.9, 139.7, 147.0, 150.3, 156.1. HRMS (TOF ES+): m/z calcd. for C24H18Cl2N3O2 [M+H]+, 450.0771; found, 450.0771. 6-(4-Chlorophenyl)-N-(4-methoxyphenethyl)-3-nitro-4-phenylpyridin-2-amin

(5t).

Yellow

solid; yield: 436 mg, 95%; Mp: 139.5–140.4 °C; IR (KBr): 3407, 1607, 1551, 1502, 1269, 1090, 1014, 855 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 2.90 (t, J = 7.5 Hz, 2H, CH2), 3.73 (s, 3H, OCH3), 3.74–3.77 (m, 2H, NCH2), 6.86–6.90 (m, 2H, ArH), 7.21 (t, J = 8.5 Hz, 3H, ArH), 7.41– 7.42 (m, 2H, ArH), 7.44–7.50 (m, 3H, ArH), 7.58–7.59 (m, 3H, ArH and NH), 8.20–8.23 (m, 2H, ArH);

13

C{1H}NMR (150 MHz, DMSO-d6): δ = 34.6, 43.5, 55.5, 110.8, 114.4, 127.7, 129.2,

129.3, 129.3, 129.4, 129.6, 130.1, 131.8, 135.7, 136.6, 137.2, 147.4, 150.8, 156.5, 158.2. HRMS (TOF ES+): m/z calcd. for C26H23ClN3O3 [M+H]+, 460.1422; found, 460.1423. N-Benzyl-4,6-diphenylpyridin-2-amine (6a). Light yellow solid; yield: 279 mg, 83%; Mp: 82.9–83.8 °C; IR (KBr): 3438, 3024, 1608, 1556, 1518, 1491, 1223, 759 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 4.65 (d, J = 6.0 Hz, 2H, NCH2), 6.76 (s, 1H, ArH), 7.21–7.52 (m, 13H,


28

Page 29 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ArH and NH), 7.74 (d, J = 7.5 Hz, 2H, ArH), 8.09 (d, J = 7.5 Hz, 2H, ArH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 44.9, 105.0, 107.1, 127.0, 127.0, 127.2, 127.9, 128.7, 128.9, 129.0, 129.2, 129.5, 139.2, 140.0, 141.4, 149.6, 155.2, 159.5. HRMS (TOF ES+): m/z calcd. for C24H21N2 [M+H]+, 337.1699; found, 337.1700. N-(4-Methoxyphenethyl)-4,6-diphenylpyridin-2-amine (6b). Light yellow; yield: 323 mg, 85%; Mp: 86.1–86.9 °C; IR (KBr): 3412, 2932, 1608, 1553, 1510, 1242, 1030, 759 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.86 (t, J = 7.5 Hz, 2H, CH2), 3.57–3.74 (m, 2H, NCH2), 3.73 (s, 3H, OCH3), 6.73 (t, J = 4.3 Hz, 2H, ArH), 6.89 (d, J = 8.5 Hz, 2H, ArH), 7.23 (d, J = 8.5 Hz, 2H, ArH), 7.35 (s, 1H, ArH), 7.41(br, 1H, NH), 7.43–7.53 (m, 5H, ArH), 7.76 (d, J = 7.3 Hz, 2H, ArH), 8.16 (d, J = 7.3 Hz, 2H, ArH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 34.9, 43.6, 55.5, 104.9, 106.8, 114.3, 127.0, 127.2, 128.9, 129.0, 129.1, 129.4, 130.1, 132.5, 139.3, 140.1, 149.5, 155.3, 158.1, 159.6. HRMS (TOF ES+): m/z calcd. for C26H25N2O [M+H]+, 381.1961; found, 381.1960. 6-(4-Fluorophenyl)-N,4-diphenylpyridin-2-amine (6c). Light yellow; yield: 309 mg, 91%; Mp: 105.4–106.3 °C; IR (KBr): 3434, 1612, 1524, 1508, 1495, 1218, 1154, 755 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 6.92–6.96 (m, 1H, ArH), 7.08 (s, 1H, ArH), 7.32–7.36 (m, 4H, ArH), 7.49 (t, J = 7.3 Hz, 1H, ArH), 7.55 (t, J = 7.5 Hz, 2H, ArH), 7.60 (s, 1H, ArH), 7.79–7.83 (m, 4H, ArH), 8.21–8.26 (m, 2H, ArH), 9.22 (br, 1H, NH);

13


107.3, 109.3, 115.9 (d, J = 21.3 Hz), 118.7, 121.1, 122.3, 127.3, 128.9, 129.2, 129.5, 136.2, 138.7, 142.1, 150.1, 154.4, 156.7, 163.2 (d, J = 245.0 Hz). HRMS (TOF ES+): m/z calcd. for C23H18FN2 [M+H]+, 341.1449; found, 341.1455. N-(4-Chlorophenethyl)-6-(4-fluorophenyl)-4-phenylpyridin-2-amine (6d). Light yellow; yield: 361 mg, 90%; Mp: 89.0–89.5 °C; IR (KBr): 3314, 2851, 1613, 1524, 1496, 1226, 1158, 766 cm-1;


29


1

Page 30 of 41

H NMR (500 MHz, DMSO-d6): δ = 2.91–2.96 (m, 2H, CH2), 3.59–3.65 (m, 2H, NCH2), 6.71 (s,

1H, ArH), 6.77 (br, 1H, NH), 7.28–7.52 (m, 10H, ArH), 7.74–7.77 (m, 2H, ArH), 8.17–8.21 (m, 2H, ArH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 35.0, 43.0, 104.9, 106.7, 115.7 (d, J = 21.3 Hz), 127.2, 128.7, 129.0, 129.1, 129.2, 129.4, 131.1, 136.6, 139.1, 139.6, 149.5, 154.3, 159.5, 163.0 (d, J = 245.0 Hz). HRMS (TOF ES+): m/z calcd. for C25H21ClFN2 [M+H]+, 403.1372; found, 403.1372. 6-(4-Fluorophenyl)-N-(4-methoxyphenethyl)-4-phenylpyridin-2-amine (6e). Light yellow; yield: 318 mg, 80%; Mp: 99.5–100.4 °C; IR (KBr): 3557, 2934, 2834, 1609, 1556, 1511, 1286, 839 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.88 (t, J = 7.5 Hz, 2H, CH2), 3.55–3.61 (m, 2H, NCH2), 3.73 (s, 3H, CH3), 6.71 (s, 1H, ArH), 6.75 (br, 1H, NH), 6.89 (d, J = 8.5 Hz, 2H, ArH), 7.21–7.53 (m, 8H, ArH), 7.76 (d, J = 7.5 Hz, 2H, ArH), 8.19–8.23 (m, 2H, ArH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 34.9, 43.5, 55.5, 104.9, 106.6, 114.3, 115.4 (d, J = 21.3 Hz), 127.2, 129.0 (d, J = 8.8 Hz), 129.2, 129.4, 130.1, 132.4, 136.6, 139.2, 149.5, 154.3, 158.1, 159.6, 163.0 (d, J = 243.8 Hz). HRMS (TOF ES+): m/z calcd. for C26H24FN2O [M+H]+, 399.1867; found, 399.1868. 4,6-Bis(4-fluorophenyl)-N-phenylpyridin-2-amine (6f). Light yellow; yield: 315 mg, 88%; Mp: 109.5–109.4 °C; IR (KBr): 3422, 1611, 1552, 1514, 1431, 1230, 1156, 823 cm-1; 19F NMR (470 MHz, DMSO-d6): δ = -113.4, -113.1; 1H NMR (500 MHz, DMSO-d6): δ = 6.92–6.97 (m, 1H, ArH), 7.05 (s, 1H, ArH), 7.33–7.40 (m, 6H, ArH), 6.60 (s, 1H, ArH), 7.81 (d, J = 7.5 Hz, 2H, ArH), 7.86–7.90 (m, 2H, ArH), 8.22–8.26 (m, 2H, ArH), 9.23 (br, 1H, NH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 107.2, 109.2, 115.9 (d, J = 21.3 Hz), 116.4 (d, J = 21.3 Hz), 118.7, 121.1, 129.2, 129.2, 129.4, 129.5, 135.1, 136.2, 142.1, 149.0, 154.5, 156.7, 163.2 (d, J = 245.0 Hz). HRMS (TOF ES+): m/z calcd. for C23H17F2N2 [M+H]+, 359.1354; found, 359.1354.


30

Page 31 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4,6-Bis(4-fluorophenyl)-N-phenethylpyridin-2-amine (6g). Light yellow; yield: 328 mg, 85%; Mp: 85.7–86.6 °C; IR (KBr): 3354, 2920, 1607, 1556, 1513, 1229, 1156, 821 cm-1;

19

F NMR

(470 MHz, DMSO-d6): δ = -113.9, -113.5; 1H NMR (500 MHz, DMSO-d6): δ = 2.95 (t, J = 7.5 Hz, 2H, CH2), 3.61–3.65 (m, 2H, NCH2), 6.70 (s, 1H, ArH), 6.77–6.79 (m, 1H, ArH), 7.22(br, 1H, NH), 7.32–7.35 (m, 9H, ArH), 7.81–7.84 (m, 2H, ArH), 8.20–8.23 (m, 2H, ArH); 13

C{1H}NMR (125 MHz, DMSO-d6): δ = 35.8, 43.3, 104.7, 106.6, 115.7 (d, J = 20.0 Hz), 116.2

(d, J = 21.3 Hz), 126.4, 128.8, 129.0 (d, J = 8.8 Hz), 129.2 (d, J = 8.8 Hz), 129.3, 135.6, 136.5, 140.5, 148.4, 154.3, 159.5, 163.0 (d, J = 243.8 Hz), 163.1 (d, J = 243.8 Hz). HRMS (TOF ES+): m/z calcd. for C25H21F2N2 [M+H]+, 387.1667; found, 387.1668. N-(4-Chlorophenethyl)-4,6-bis(4-fluorophenyl)pyridin-2-amine (6h). Light yellow; yield: 336 mg, 80%; Mp: 79.8–80.2 °C; IR (KBr): 3346, 2927, 1608, 1554, 1513, 1231, 1155, 823 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.92–2.95 m, 2H, CH2), 3.60–3.63 (m, 2H, NCH2), 6.68 (s, 1H, ArH), 6.77 (br, 1H, NH), 7.28–7.37 (m, 9H, ArH), 7.79–7.83 (m, 2H, ArH), 8.18–8.20 (2H, ArH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 35.2, 43.0, 104.8, 106.6, 115.7 (d, J = 21.3 Hz), 116.2 (d, J = 21.3 Hz), 128.7, 129.0, 129.1, 129.3, 129.3, 131.1, 135.5, 136.5, 139.6, 148.4, 154.3, 159.5, 163.0 (d, J = 246.3 Hz). HRMS (TOF ES+): m/z calcd. for C25H20ClF2N2 [M+H]+, 421.1278; found, 421.1278. 6-(4-Chlorophenyl)-N-phenethyl-4-phenylpyridin-2-amine (6i). Light yellow; yield: 315 mg, 82%; Mp: 102.0–102.9 °C; IR (KBr): 3348, 3026, 1605, 1553, 1426, 1348, 826, 762 cm-1;

19

F

NMR (470 MHz, DMSO-d6): δ = -114.8, -109.9; 1H NMR (500 MHz, DMSO-d6): δ = 2.95 (t, J = 7.5 Hz, 2H, CH2), 3.61–3.67 (m, 2H, NCH2), 6.75 (s, 1H, ArH), 6.80–6.84 (m, 1H, ArH), 7.21–7.23 (m, 1H, NH), 7.32 (d, J = 5.0 Hz, 4H, ArH), 7.39 (d, J = 1.0 Hz, 1H, ArH), 7.46 (d, J = 7.5 Hz, 1H, ArH), 7.50–7.54 (m, 4H, ArH), 7.77 (d, J = 7.0 Hz, 2H, ArH), 8.17–8.21 (m, 2H,


31


ArH);

13

Page 32 of 41

C{1H}NMR (125 MHz, DMSO-d6): δ = 35.8, 43.3, 105.4, 106.9, 126.5, 127.2, 128.7,

128.8, 128.9, 129.2, 129.4, 133.7, 138.9, 139.1, 140.5, 149.5, 154.0, 159.6. HRMS (TOF ES+): m/z calcd. for C25H22ClN2 [M+H]+, 385.1466; found, 385.1465. 6-(4-Chlorophenyl)-N-(4-fluorobenzyl)-4-phenylpyridin-2-amine (6j). Light yellow; yield: 349 mg, 90%; Mp: 87.5–88.4 °C; IR (KBr): 3389, 2892, 1611, 1519, 1387, 1224, 1104, 826 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 4.61–4.64 (m, 2H, NCH2), 6.77 (s, 1H, ArH), 7.15 (t, J = 8.8 Hz, 2H, ArH), 7.31 (br, 1H, NH), 7.39 (s, 1H, ArH), 7.44–7.52 (m, 7H, ArH), 7.75 (d, J = 7.5 Hz, 2H, ArH), 8.11–8.15 (m, 2H, ArH);

13

C{1H}NMR (125 MHz, DMSO-d6): δ = 44.1, 105.4,

107.2, 115.4 (d, J = 21.3 Hz), 127.2, 128.7, 128.9, 128.7, 129.3, 129.4, 129.7 (d, J = 7.5 Hz), 133.8, 137.5, 138.7, 139.0, 149.7, 153.9, 159.3, 161.5 (d, J = 240.0 Hz). HRMS (TOF ES+): m/z calcd. for C24H19ClFN2 [M+H]+, 389.1215; found, 389.1215. 6-(4-Chlorophenyl)-N-(4-methoxyphenethyl)-4-phenylpyridin-2-amine (6k). Light yellow; yield: 381 mg, 92%; Mp: 141.2–141.1 °C; IR (KBr): 3347, 2833, 1607, 1552, 1511, 1246, 835, 761 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.88 (t, J = 7.5 Hz, 2H, CH2), 3.56–3.74 (m, 2H, NCH2), 3.73 (s, 3H, OCH3), 6.74 (s, 1H, ArH), 6.79 (br, 1H, NH), 6.89 (d, J = 8.5 Hz, 2H, ArH), 7.23 (d, J = 8.5 Hz, 2H, ArH), 7.38 (s, 1H, ArH), 7.44–7.53 (m, 5H, ArH), 7.76 (d, J = 7.0 Hz, 2H, ArH), 8.17–8.21 (m, 2H, ArH);

13

C{1H}NMR (125 MHz, DMSO-d6): δ = 34.9, 43.5, 55.5,

105.3, 106.8, 114.3, 127.2, 128.7, 128.9, 129.2, 129.4, 130.1, 132.4, 133.7, 138.9, 139.1, 149.5, 154.0, 158.1, 159.6. HRMS (TOF ES+): m/z calcd. for C26H24ClN2O [M+H]+, 415.1572; found, 415.1571. 6-(3-Nitrophenyl)-N-phenyl-4-(p-tolyl)pyridin-2-amine (6l). Light yellow; yield: 335 mg, 88%; Mp: 124.5–125.4 °C; IR (KBr): 3387, 1620, 1534, 1500, 1443, 1343, 816, 748 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.39 (s, 3H, ArCH3), 6.97 (t, J = 7.3 Hz, 1H, ArH), 7.14 (s, 1H, ArH),


32

Page 33 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.32–7.39 (m, 4H, ArH and NH), 7.75–7.82 (m, 6H, ArH), 8.26–8.30 (m, 1H, ArH), 8.63–8.67 (m, 1H, ArH), 9.02–9.06 (m, 1H, ArH), 9.31 (s, 1H, ArH); 13C{1H}NMR (125 MHz, DMSO-d6): δ = 21.3, 108.1, 109.7, 118.9, 121.4, 121.5, 123.8, 127.2, 129.2, 130.2, 130.7, 133.2, 135.4, 139.3, 141.3, 141.9, 148.9, 150.2, 152.7, 156.8. HRMS (TOF ES+): m/z calcd. for C24H20N3O2 [M+H]+, 382.1550; found, 382.1550. N-(4-Fluorobenzyl)-6-(3-nitrophenyl)-4-(p-tolyl)pyridin-2-amine (6m). Light yellow; yield: 330 mg, 80%; Mp: 108.3–109.2 °C; IR (KBr): 3425, 2933, 1607, 1501, 1347, 1217, 820, 760 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 2.37 (s, 3H, ArCH3), 4.59–4.63 (m, 2H, NCH2), 6.83 (s, 1H, ArH), 7.15 (t, J = 8.8 Hz, 2H, ArH), 7.32 (d, J = 7.5 Hz, 2H, ArH), 7.43–7.52 (m, 4H, ArH and NH), 7.68–7.75 (m, 3H, ArH), 8.22 (d, J = 8.0 Hz, 1H, ArH), 8.55 (d, J = 7.5 Hz, 1H, ArH), 8.89 (s, 1H, ArH);

13

C{1H}NMR (125 MHz, DMSO-d6): δ = 21.2, 44.3, 105.9, 107.6,

115.4 (d, J = 21.3 Hz), 121.4, 123.5, 127.1, 129.7 (d, J = 7.5 Hz), 130.0, 130.4, 133.2, 135.8, 137.4, 139.0, 141.6, 148.8, 149.7, 152.6, 159.4, 161.5 (d, J = 240.0 Hz). HRMS (TOF ES+): m/z calcd. for C25H21FN3O2 [M+H]+, 414.1612; found, 414.1610. N-(4-methoxyphenethyl)-6-(3-nitrophenyl)-4-(p-tolyl)pyridin-2-amine (6n). Light yellow; yield: 351 mg, 80%; Mp: 116.5–117.4 °C; IR (KBr): 3414, 2923, 1608, 1534, 1513, 1342, 1247, 817 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 2.38 (s, 3H, ArCH3), 2,88 (t, J = 7.6 Hz, 2H, CH2), 3.52–3.62 (m, 2H, NCH2), 3.73 (s, 3H, OCH3), 6.78 (s, 1H, ArH), 6.85–6.93 (m, 3H, ArH), 7.23–7.29 (m, 2H, ArH), 7.33 (d, J = 7.9 Hz, 2H, ArH), 7.52 (s, 1H, ArH), 7.70 (d, J = 7.9 Hz, 2H, ArH), 7.73–7.79 (m, 1H, ArH), 8.22–8.28 (m, 1H, ArH), 8.61 (d, J = 7.8 Hz, 1H, ArH), 9.02 (s, 1H, NH); 13C{1H}NMR (150 MHz, DMSO-d6): δ = 21.3, 35.0, 43.7, 55.5, 107.1, 114.3, 121.3, 123.5, 127.1, 130.0, 130.2, 130.5, 132.3, 133.2, 135.8, 138.9, 141.8, 148.9, 149.5, 152.5, 158.1, 159.7. HRMS (TOF ES+): m/z calcd. for C27H26N3O3 [M+H]+, 440.1969; found, 440.1969.


33


Page 34 of 41

4-(4-chlorophenyl)-N,6-diphenylpyridin-2-amine (6o). Light yellow; yield: 316 mg, 89%; Mp: 91.1–92.0 °C; IR (KBr): 3425, 1610, 1528, 1494, 1427, 1378, 1304, 821 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 6.91–6.97 (m, 1H, ArH), 7.08 (s, 1H, ArH), 7.31–7.37 (m, 2H, ArH), 7.42–7.48 (m, 1H, ArH), 7.50–7.56 (m, 2H, ArH), 7.58–7.64 (m, 3H, ArH), 7.81–7.88 (m, 4H, ArH), 8.16–8.21 (m, 2H, ArH), 9.28 (br, 1H, NH);

13


107.3, 109.2, 118.6, 121.1, 127.1, 129.1, 129.1, 129.2, 129.4, 129.6, 134.3, 137.6, 139.6, 142.1, 148.6, 155.6, 156.7. HRMS (TOF ES+): m/z calcd for C23H18ClN2 [(M+H)+], 357.1153; found, 357.1151. 2,4-di(furan-2-yl)-3-methyl-6-(piperidin-1-yl)pyridine (6p). Yellow solid; yield: 247 mg, 84%; Mp: 102.2–103.2 °C; IR (KBr): 3122, 2944, 1617, 1553, 1493, 1445, 1242 cm-1; 1H NMR (600 MHz, CDCl3): δ = 1.56–1.60 (m, 6H, 3CH2), 3.52–3.57 (m, 4H, 2CH2), 6.39–6.43 (m, 2H, CH), 6.73–6.78 (m, 2H, CH), 6.90–6.95 (m, 1H, CH ), 7.19 (br, 1H, NH), 7.38–7.43 (m, 1H, CH ); 13

C{1H}NMR (150 MHz, CDCl3): δ = 24.8, 25.6, 46.3, 99.6, 102.6, 107.7, 108.0, 111.8, 111.8,

139.4, 142.6, 142.9, 148.0, 152.7, 154.8, 159.8. HRMS (TOF ES+): m/z calcd for C18H19N2O2 [(M+H)+], 295.1441; found, 295.1441. 

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 4j, 5m and 6j (CCDC 1870261, CCDC 1870252 ＆CCDC 1870253). This material is available free of charge via the Internet at http://pubs.acs.org. 

AUTHOR INFORMATION

Corresponding Authors


34

Page 35 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


*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 Author Contributions ‡

These authors contributed equally to this paper.

Notes The authors declare no competing financial interest. 

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Nos.

21662042, 81760621, 21362042, U1202221), the Program for Changjiang Scholars and Innovative Research Team in University (IRT17R94), the Natural Science Foundation of Yunnan Province (2017FA003). 

REFERENCES (1) (a) Basit, S.; Ashraf, Z.; Lee, K.; Latif, M. First macrocyclic 3rd-generation ALK inhibitor

for treatment of ALK/ROS1 cancer: Clinical and designing strategy update of lorlatinib. Eur. J. Med. Chem.2017, 134, 348–356. (b) Nishiguchi, G. A.; Rico, A.; Tanner, H.; Aversa, R. J.; Taft, B. R.; Subramanian, S.; Setti, L.; Burger, M. T.; Wan, L.; Tamez, V.; Smith,A.; Lou, Y.; Barsanti, P. A.; Appleton, B. A.; Mamo, M.; Tandeske, L.; Dix, I.; Tellew, J. E.; Huang, S.; Mathews Griner, L. A.; Cooke, V. G.; Abbema, A. V.; Merritt, H. et.al. Design and Discovery of N-(2-Methyl-5′-morpholino-6′-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3′-bipyridin]-5-yl)-3-(trifle -oromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting


35


Page 36 of 41

RAS Mutant Cancers. J. Med. Chem. 2017, 60, 4869−4881. (2) Siu, M.; Ghosh, A. S.; Lewcok, J. W. Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration. J. Med. Chem. 2018, 61, 8078–8087. (3) Schoepfer, J.; Jahnke, W..; Berellini, G.; Buonamici, S.; Cotesta, S. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J. Med. Chem. 2018, 61, 8120–8135. (4) Liu, N.; Tu, J.; Dong, G.; Sheng, C. Emerging New Targets for the Treatment of Resistant Fungal Infections. J. Med. Chem. 2018, 61, 5484–5511. (5) (a) Torborg, C.; Beller, M. Recent Applications of Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries. Adv. Synth. Catal. 2009, 351, 3027–3043. (b) Hartwig, J. F. Evolution of a Fourth Generation Catalyst for the Amination and Thioetherification of Aryl Halides. Acc. Chem. Res. 2008, 41, 1534–1544. (c) Schlummer, B.; Scholz, U. Palladium-Catalyzed C-N and C-O Coupling-A Practical Guide from an Industrial Vantage Point. Adv. Synth. Catal. 2004, 346, 1599–1626. (d) Littke, A. F.; Fu, G. C. Palladium-Catalyzed Coupling Reactions of Aryl Chlorides. Angew. Chem., Int. Ed. 2002, 41, 4176–4211. (6) (a) Brusoe, A. T.; Hartwig, J. F. Palladium-Catalyzed Arylation of Fluoroal-kylamines. J. Am. Chem. Soc. 2015, 137, 8460–8468. (b) Park, N. H.; Vinogradova, E. V.; Surry, D. S.; Buchwald, S. L. Design of New Ligands for the Palladium-Catalyzed Arylation of α-Branched Secondary Amines. Angew. Chem., Int. Ed. 2015, 54, 8259–8262. (c) Green, R. A.; Hartwig, J. F. Palladium-Catalyzed Amination of Aryl Chlorides and Bromides with Ammonium Salts. Org. Lett. 2014, 16, 4388–4391.


36

Page 37 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(7) (a) Wang, D.; Kuang, D.; Zhang, F.; Liu, Y.; Ning, S. Ligand free copper-catalyzed Narylation of heteroarylamines. Tetrahedron Lett. 2014, 55, 7121–7123. (b) Monnier, F.; Taillefer, M. Catalytic C-C, C-N, and C-O Ullmann-Type Coupling Reactions. Angew. Chem., Int. Ed. 2009, 48, 6954–6971. (c) Liu, Y.; Bai, Y.; Zhang, J.; Li, Y.; Jiao, J.; Qi, X. Optimization of the Conditions for Copper‐Mediated N‐Arylation of Heteroarylamines. Eur. J. Org. Chem. 2007, 36, 6084–6088. (8) Mantri, M.; de Graaf, O.; van Veldhoven, J.; Göblyös, A.; von Frijtag Drabbe Künzel, J. K.; Mulder-Krieger, T.; Link, R.; de Vries, H.; Beukers, M. W.; Brussee, J.; Ijzerman, A. P. 2Amino-6-furan-2-yl-4-substituted Nicotinonitriles as A2A Adenosine Receptor Antagonists. J. Med. Chem. 2008, 51, 4449–4455. (9) Paluchowska, M. H.; Bojarski, A. J.; Bugno, R.; Charakchieva-Minol, S.; Wesolowska, A. Modification of the Structure of 4, 6-Disubstituted 2-(4-Alkyl-1-piperazinyl)pyridines: Synthesis and Their 5-HT2A Receptor Activity. Arch. Pharm. (Weinheim) 2003, 336, 104–110. (10) Girgis, A. S.; Mishriky, N.; Farag, A. M.; El-Eraky, W. I.; Farag, H. Synthesis of new 3pyridinecarboxylates of potential vasodilation properties. Eur. J. Med. Chem. 2008, 43, 1818– 1827. (11) Girgis, A. S.; Tala, S. R.; Oliferenko, P. V.; Oliferenko, A. A.; Katritzky, A. R. Computer-assisted rational design, synthesis, and bioassay of non-steroidal anti-inflammatory agents. Eur. J. Med. Chem. 2012, 50, 1–8. (12) Kumar, D.; Vemula, S. R.; Cook, G. R. Merging C–H Bond Functionalization with Amide Alcoholysis: En Route to 2-Aminopyridines. ACS Catal. 2016, 6, 3531–3536. (13) Wu, Q.; Zhang, Y.; Cui, S. Divergent Syntheses of 2-Aminonicotinonitriles and Pyrazolines by Copper-Catalyzed Cyclization of Oxime Ester. Org. Lett. 2014, 16, 1350–1353.


37


Page 38 of 41

(14) Cheng, G.; Weng, Y.; Yang, X.; Cui, X. Base-Promoted N-Pyridylation of Heteroarenes Using N-Propargyl Enaminones as Equivalents of Pyridine Scaffolds. Org. Lett. 2015, 17, 3790– 3793. (15) Weng, Y-X.; Kuai, C-S.; Lv, W-W.; Cheng, G-L. Synthesis of 2-Aminopyridines via a Base-Promoted Cascade Reaction of N-Propargylic β-Enaminones with Formamides. J. Org. Chem. 2018, 83, 5002–5008. (16) (a) Wang, K.-M.; Yan S.-J.; Lin, J. Heterocyclic Ketene Aminals: Scaffolds for Heterocycle Molecular Diversity. Eur. J. Org. Chem. 2014, 1129–1145. (b) Huang Z.-T.; Wang, M.-X. Heterocyclic Ketene Aminals. Heterocycles, 1994, 37, 1233–1262. (17) (a) Chen, N.; Meng, X.; Zhu, F.; Cheng, J.; Shao, X.; Li, Z. J. Tetrahydroindeno[1′,2′:4,5]pyrrolo[1,2-a]imidazol-5(1H)-ones as Novel Neonicotinoid Insecticides: Reaction Selectivity and Substituent Effects on the Activity Level. Agric. Food Chem. 2015, 63, 1360−1369. (b) Bao, H.; Shao, X.; Zhang, Y.; Deng, Y.; Xu, X.; Liu, Z.; Li, Z. J. Specific Synergist for Neonicotinoid Insecticides: IPPA08, a cis-Neonicotinoid Compound with a Unique Oxabridged Substructure. Agric. Food Chem. 2016, 64, 5148−5155. (c) Huang, C.; Yan, S.-J.; Zeng, X.-H.; Dai, X.-Y.; Zhang, Y.; Qing, C.; Lin, J. Biological evaluation of polyhalo 1,3diazaheterocycle fused isoquinolin-1(2H)-imine derivatives. Eur. J. Med. Chem. 2011, 46, 1172– 1180. (d) Yu, F.-C.; Lin, X.-R.; Liu, Z.C.; Zhang, J.-H.; Liu, F.-F.; Wu, W.; Ma, Y.-L.; Qu, W.W.; Yan, S.-J.; Lin, J. Beyond the Antagonism: Self-Labeled Xanthone Inhibitors as Modeled “Two-in-One” Drugs in Cancer Therapy. ACS Omega. 2017, 2, 873−889. (18) (a) Li, M.; Shao, P.; Wang, S.-W.; Kong, W.; Wen, L.-R. Four-Component Cascade Heteroannulation

of

Heterocyclic

Ketene

Aminals:

Synthesis

of

Functionalized

Tetrahydroimidazo[1,2-a]pyridine Derivatives. J. Org. Chem. 2012, 77, 8956–8967. (b)


38

Page 39 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Suryawanshi, S. N.; Pandey, S.; Rashmirathi; Bhatt, B. A.; Gupta, S. Chemotherapy of leishmaniasis Part VI: Synthesis and bioevaluation of some novel terpenyl S,N- and N,N-acetals Eur. J. Med. Chem. 2007, 42, 511−516. (c) Chen, L.; Huang, R.; Du, X.-X.; Yan, S.-J.; Lin, J. One-Pot Synthesis of Highly Functionalized Bicyclic Imidazopyridinium Derivatives in Ethanol. ACS Sustainable Chem. Eng. 2017, 5, 1899−1905. (d) Ma, Y.-L.; Wang, K.-M.; Huang, R.; Lin, J.; Yan, S.-J. An environmentally benign double Michael addition reaction of heterocyclic ketene aminals with quinone monoketals for diastereoselective synthesis of highly functionalized morphan derivatives in water. Green Chem. 2017, 19, 3574−3584. (19) (a) Wang, B-Q.; Zhang, C.-H.; Tian, X.-X.; Lin, J.; Yan, S.-J. Cascade Reaction of Isatins with 1,1-Enediamines: Synthesis of Multisubstituted Quinoline-4-carboxamides. Org. Lett. 2018, 20, 660–663. (b) Zhang, C.-H.; Huang, R.; Hu, X.-M.; Lin, J.; Yan, S.-J. Three-Component SiteSelective Synthesis of Highly Substituted 5H-Chromeno-[4,3-b]pyridines. J. Org. Chem. 2018, 83, 4981–4989. (c) Du, X.-X.; Huang, R.; Yang, C.-L.; Lin, J.; Yan, S.-J. Synthesis and evaluation of the antitumor activity of highly functionalised pyridin-2-ones and pyrimidin-4-ones RSC Adv. 2017, 7, 40067–40073. (20) Mertens, H.; Troschuetz, R. Nitroketenaminale, 5. Mitt*: Synthese von N2-substituierten 2-Amino-3-nitropyridinen als Vorstufen von Pyrido[2,3-b]pyrazinen (3-Desazapteridinen). Arch. Pharm. 1987, 320, 1143–1149. (21) (a) Chen, J.; Chang, D.; Xiao, F.; Deng, G.-J. Four-component quinazoline synthesis from simple anilines, aromatic aldehydes and ammonium iodide under metal-free conditions. Green Chem. 2018, 20, 5459–5463. (b) Deb, M. L.; Borpatra, P. J.; Baruah, P. K. A one-pot catalyst/external oxidant/solvent-free cascade approach to pyrimidines via a 1,5-hydride transfer. Green Chem. 2019, 21, 69–74.


39


Page 40 of 41

(22) (a) Li, Y.; Xu, H.; Xing, M.; Huang, F.; Jia, J.; Gao, J. Iodine-Promoted Construction of Polysubstituted 2,3-Dihydropyrroles from Chalcones and β-Enamine Ketones (Esters). Org. Lett. 2015, 17, 3690–3693. (b) Zhang, H.; Shen, J.; Cheng, G.; Wu, B.; Cu, X. Base‐Promoted Synthesis of 2,4,6‐Triarylpyridines from Enaminones and Chalcones. Asian J. Org. Chem. 2018, 7, 1089–1092. (23) (a) Chen, X.; Bai, H.; Huang, C. Concise Synthesis of Quinolinone Derivatives. Chin. J. Org. Chem. 2017, 37, 881–888. (b) Mertens, H.; Troschuetz, R.; Roth, H. J.; Synthese primärer Nitroketenaminale. Arch. Pharm. (Weinheim, Germany), 1986, 319, 161−167. (c) Kenda, B.; Quesnel, Y.; Ates, A.; Michel, P.; Turet, L.; Mercier. J.; WO 2006128693 A2. (d) Hu, X.-M.; Luo, D.-Y.; Zi, Q.-X.; Lin, J.; Yan, S.-J. Diastereoselective Synthesis of Morphan Derivatives by Michael and Hetero-Michael Addition of 1,1-Enediamines to Quinone Monoketals. ACS Omega 2017, 3, 8−21.


40

Page 41 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC Graphic

Highly selective synthesis of 2-amino-4,6-diarylpyridine derivatives by the cascade reaction of 1,1-enediamines with α,β-unsaturated ketones Qin Luo,‡,† Rong Huang, ‡,† Qiang Xiao,† Yuan Yao,† Jun Lin*,† and Sheng-Jiao Yan*,†

A general and concise method was developed for the synthesis of 2-amino-4,6-diarylpyridine derivatives 4–6 through the cascade reaction, which includes the Michael addition, intramolecular cyclization, aromatization and/or loss of HNO2, of different types of α,βunsaturated ketones 1 and 1,1-enediamines 2–3 in 1,4-dioxane promoted by the base Cs2CO3 or piperidine.


41

Highly selective synthesis of 2-amino-4,6-diarylpyridine derivatives by

Recommend Documents