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Article Cite This: J. Org. Chem. 2018, 83, 4981−4989

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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* 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 S Supporting Information *

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 5Hchromeno[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 a 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 byproducts, ease of processing for isolation and purification, high yield, and 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,β-unsaturated aldehydes that use C1 as a 1,4-Michael acceptor and C4 as a 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, and 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) © 2018 American Chemical Society

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 The chromenopyridines, which are a combination of pyridines and chromenones, have a wide range of biological properties, including antitumor (Figure 1, compounds A and B),15 antibacterial (compound C),16 antipsychotic (compound D), nervous system depressant (Figure 1, schumanniophytine), and anti-inflammatory (amlexanox)17 effects. Consequently, chromenopyridines have aroused extensive research interest 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 arylpropynyloxy-benzonitriles 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-2-oxo-2H-chromene3-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 an important contribution to the synthesis of chromenopyridines, they usually have some shortcomings, such as requiring a high temperature, metal catalyst, multisteps, etc. Accordingly, a highly efficient and mild multicomponent one-pot cascade reaction for the synthesis of Received: January 12, 2018 Published: April 12, 2018 4981

DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989

Article

The Journal of Organic Chemistry Scheme 1. Synthetic Routes of Chromenopyridines

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

Table 1. Optimization of the Reaction Conditions for the Model reactiona

entry

solvent

catalyst

T (°C)

t (min)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

acetone (6 mL) THF (6 mL) EtOH (6 mL) CH3CN (6 mL) H2O (6 mL) 1,4-dioxane (6 mL) EtOH (6 mL) EtOH (6 mL) EtOH (6 mL) EtOH (4 mL) EtOH (5 mL) EtOH (8 mL) EtOH (4 mL) EtOH (4 mL) EtOH (4 mL) EtOH (4 mL)

HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HOAc MeSO3Hc HCl TFA

reflux reflux reflux reflux reflux reflux 40 50 60 50 50 50 50 50 50 50

24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24

56 52 64 40 28 51 63 84 78 85 84 81 79 64 80 81

a

Reaction conditions: 1a (0.5 mmol) and 2a (0.5 mmol) were dissolved in the EtOH (4 mL) and stirred for many hours, and then one drop of acid was added. bIsolated yield based on 1a. cMeSO3H (0.05 mmol).

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). On the basis of these research works, here, we report a concise, efficient, and environment friendly method for the synthesis of novel highly functionalized 5H-chromeno[4,3b]pyridines by a three-component, one-step cascade reaction (Scheme 1).

chromenopyridine derivatives is of interest and is desirable and urgently needed. Our group used 3-formylchromones as the α,β-unsaturated aldehydes that use C1 as a 1,4-Michael acceptor and C4 as a 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 3formylchromones to provide C1 as a 1,4-Michael acceptor and C4 as a 1,2-addition acceptor to react with EDAMs catalyzed by 4982

DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989

Article

The Journal of Organic Chemistry Table 2. Synthesis of 5H-Chromeno[4,3-b]pyridines 4aa−4eka

entry

1/R

2/R′

4

yieldb (%)

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

1a/H 1a/H 1a/H 1a/H 1a/H 1a/H 1a/H 1a/H 1a/H 1a/H 1a/H 1a/H 1b/F 1d/F 1b/F 1b/F 1b/F 1b/F 1b/F 1b/F 1b/F 1c/Cl 1c/Cl 1c/Cl 1d/NO2 1d/NO2 1d/NO2 1e/Me 1e/Me 1e/Me

2a/n-butyl 2b/H 2c/cyclohexyl 2d /4-Fphenyl 2e/furan-2-ylmethyl 2f/benzyl 2g/4-Fbenzyl 2h/4-Clbenzyl 2i/phenethyl 2j/4-Fphenethyl 2k/4-Clphenethyl 2l/4-methoxyphenethyl 2a/n-butyl 2e/furan-2-ylmethyl 2f/benzyl 2g/4-Fbenzyl 2h/4-Clbenzyl 2i/phenethyl 2j/4-Fphenethyl 2k/4-Clphenethyl 2l/4-methoxyphenethyl 2a/n-butyl 2f/benzyl 2i/phenethyl 2a/n-butyl 2c/cyclohexyl 2f/benzyl 2c/cyclohexyl 2f/benzyl 2k/4-Fphenethyl

4aa 4ab 4ac 4ad 4ae 4af 4ag 4ah 4ai 4aj 4ak 4al 4ba 4be 4bf 4bg 4bh 4bi 4bj 4bk 4bl 4ca 4cf 4ci 4da 4dc 4df 4ec 4ef 4ek

85 74 83 81 86 85 84 84 85 85 84 85 87 87 91 89 88 90 87 91 87 89 90 89 81 82 81 80 82 83

a

Reaction conditions: 1 (0.5 mmol) and 2 (0.5 mmol) were dissolved in the EtOH (4 mL) and stirred for 24 h, and then one drop of HClO4 was added. bIsolated yield based on 1.

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, and 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 and 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 °C (Table 1, entry 10). Raising the temperature decreased the reaction time, but too low or too high of a temperature was unfavorable for the reaction (Table 1, entries 3 and 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 and 10−12). 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 as follows: temperature under 50 °C, for

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-formylchromones are concurrently present in the multicomponent cascade reactions. To the best of our knowledge, this is the first example of the synthesis of novel 5H-chromeno[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 advantages, including convenience of operation, short reaction times, a green solvent, and simple purification by washing the crude products with ethanol.

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RESULTS AND DISCUSSION To optimize the reaction conditions for the synthesis of 5Hchromeno[4,3-b]pyridines 4aa, 3-formylchromone 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 4983

DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989

Article

The Journal of Organic Chemistry Table 3. 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 stirred for 24 h, and then 3 (0.6 mmol) and one drop of HClO4 were added. bIsolated yield based on 1.

Scheme 2. Mechanism Hypotheses for the Synthesis of Target Compounds 4

24 h in 4 mL of 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 1,1enediamines. Different 3-formylchromones 1 and 1,1-enediamines 2 were used in this protocol (Table 2). First, 3-formylchromones 1a was used as a substrate to react with different 1,1-enediamines 2a−2l (Table 2, entries 1−12). The results revealed that the substituted group on the 1,1-enediamines 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 2nitroethene-1,1-diamine 2b as a 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 produced more byproducts. Second, the 6-fluoro-3-formylchromone 1b reacted with 1,1-enediamines 2a and 2e−2l (Table 2, entries 13−21), and the results indicated that the substituted group on the 1,1enediamines 2 does not have a prominent influence on the yield (Table 2, entries 13−21). Finally, the other three 3formylchromones 1c−1e were also used in this method. We also produced the target compounds with excellent yields (Table 2, entries 22−30). Overall, we conclude that the electron-drawing groups on the 3-formylchromone 1 generally can produce higher yields than electron-donating groups (1b,

1c > 1a > 1e) (Table 2, entries 1−12 and 28−30 vs 13−24). However, the NO2-substituented 3-formylchromone 1d did not conform with this law and only produced a lower yield (Table 2, entries 25−27 vs 1−24 and 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 in place of ethanol. The optimized conditions successfully produced the substituted 5H-chromeno[4,3-b]pyridines in good to excellent yields (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). A proposed mechanism for this cascade reaction is shown in Scheme 2. 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; this step has a very high site selectivity. Second, 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 4984

DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989

Article

The Journal of Organic Chemistry

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 1,1enediamine 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 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);13C 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-2amine (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), 8.20−8.22 (m, 1H, ArH), 8.36 (br, 1H, NH), 8.37 (s, 1H, CH); 13 C 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 cm−1; 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); 13C NMR (125 MHz, CDCl3) δ 15.1, 38.3,

underwent a 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 is essentially completely environment friendly. It must be noted that the cascade reaction has very high regioselectivity. As a result, only the target products 4 and 4′ were 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 a 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 αC of 1,1-enediamine 2 attacks the aldehyde group of the 3formylchromone 1 to generate the intermediate 5 via a 1,2addition 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 °C for 12 h and subsequently one drop of HClO4 was added to the mixture. Then, we immediately injected the reaction mixture into the high-pressure liquid chromatography-high-resolution mass spectrometry (HPLCHRMS) system. The molecular ion peak appeared in the highresolution mass spectrometry. (HRMS (TOF ES+): m/z calcd for C16H18N3O4 [M]+, 316.1298; found, 316.1292. See the Supporting Information, which is the HRMS spectra of intermediate 9.) Products 4 were characterized by proton nuclear magnetic resonance (1H NMR), 13C 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 no. 1578705.)

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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 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[4,3b]pyridines by the reaction of 3-formylchromone, 1,1-enediamines, and alcohol or amine derivatives.

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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, 13C 150 MHz) spectrometer. Chemical shifts (δ) are expressed in ppm; coupling constants (J) are given in hertz (Hz), and deuterated CDCl3 and DMSO-d6 were used as solvents. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 unit using KBr pellets. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF254. The melting points were determined on an XT-4A melting point apparatus and are uncorrected. High-resolution mass spectra (HRMS-TOF) were performed on an AutoSpec Premier P776 unit. X-ray diffraction was obtained by an APEX DUO diffractometer. 4985

DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989

Article

The Journal of Organic Chemistry

(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); 13C 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]-pyridin2-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, 150.4, 151.7, 152.9, 158.17 (d, J = 245.0 Hz); IR (KBr) 3447, 1624, 1384, 1268, 1168, 1076 cm−1; 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); 13C 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]pyridin2-amine (4bf): yellow solid; yield 180 mg, 91%; mp 154−156 °C; 1H NMR (600 MHz, CDCl3) 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[4,3b]pyridin-2-amine (4bg): yellow solid; yield 184 mg, 89%; mp 200− 202 °C; 1H NMR (600 MHz, DMSO-d6) δ 1.08 (t, 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); 13C 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),

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 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]pyridin2-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); 13 C 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, 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); 13C 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); 13C 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 Hz, CH3), 3.00−3.03 (m, 2H, ArCH2), 3.77−3.80 (m, 1H, OCH2), 3.94−4.01 4986

DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989

Article

The Journal of Organic Chemistry

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] pyridin2-amine (4ca): yellow solid; yield 168 mg, 89%; mp 136−138 °C; 1 H 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]pyridin2-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, 1H, OCH), 7.00−7.01 (d, 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); 13C 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-2amine (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); 13C 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-2amine (4dc): yellow solid; 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); 13C 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-2amine (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); 13C NMR (150 MHz, CDCl3) δ

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[4,3b]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); 13C 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); 13C 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), 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); 13C 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); 13C 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 444.1119. 5-Ethoxy-9-fluoro-N-(4-methoxyphenethyl)-3-nitro-5Hchromeno[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); 13C 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; 4987

DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989

Article

The Journal of Organic Chemistry

(br, 1H, NH); 13C 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-2amine (4c′): yellow solid; 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 (d, 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); 13C NMR (125 MHz, 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-2amine (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); 13C 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), 3.74−3.77 (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); 13C 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); 13 C 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, 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.

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 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]pyridin2-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 mixture. The reaction mixture was stirred at 50 °C until full consumption of 1,1enediamine 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 4988

DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989

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The Journal of Organic Chemistry

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00099. Spectroscopic and analytical data as well as the original copy of 1H and 13C NMR spectra of all new compounds (PDF) X-ray crystallography of compound 4bg (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. 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.

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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 (21662042, 81760621, 21362042, and U1202221), the Natural Science Foundation of Yunnan Province (2017FA003), and 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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DOI: 10.1021/acs.joc.8b00099 J. Org. Chem. 2018, 83, 4981−4989