Construction of Fully Substituted 2-Pyridone Derivatives via Four

Sep 19, 2018 - ... 2-Pyridone Derivatives via Four-Component Branched Domino Reaction utilizing Microwave Irradiation. Hairui Bai , Rongrong Sun , Shi...
0 downloads 0 Views 3MB Size
Download PDF
Article Cite This: J. Org. Chem. 2018, 83, 12535−12548

pubs.acs.org/joc

Construction of Fully Substituted 2‑Pyridone Derivatives via Four-Component Branched Domino Reaction Utilizing Microwave Irradiation Hairui Bai,†,§ Rongrong Sun,†,§ Shitao Liu,† Lijuan Yang,† Xuebing Chen,*,‡ and Chao Huang*,† †

Downloaded via UNIV OF LOUISIANA AT LAFAYETTE on October 19, 2018 at 09:40:35 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Engineering Research Center of Biopolymer Functional Materials of Yunnan, School of Chemistry and Environment, Yunnan Minzu University, Kunming 650500, P.R. China ‡ Key Laboratory of Natural Pharmaceutical and Chemical Biology of Yunnan, School of Science, Honghe University, Mengzi 661199, P.R. China S Supporting Information *

ABSTRACT: Microwave irradiation, four-component branched domino reaction of methyl acetoacetate/2,4-pentanedione, diethyl malonate, triethyl orthoformate and amines offering an extremely efficient strategy for the construction of fully substituted 2-pyridone derivatives under sustainable conditions is established. This self-sorting branched domino transformation is proposed to proceed separate through N-nucleophilic addition and imine-enamine tautomerization/condensation reaction generated from enamino ester and diethyl ethoxymethylenemalonate, and then would be subjected to an aza-ene reaction and intramolecular cyclization mechanism to afford the 2-pyridones with only water and ethanol as byproducts. The simple experimental procedure, high bond-forming efficiency, step and atom economy, inexpensive readily available starting materials, moderate to excellent yields, and good functional group compatibility are other noteworthy advantages of this method.

■

INTRODUCTION The U.S. Environmental Protection Agency (EPA) defined the “green chemistry” concept as “the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances”.1,2 In the green chemistry or sustainable chemistry field, the ideal synthesis should be a combination of a number of environmental, health, safety and economic factors.3 Toward fulfilling these goals, microwave irradiation technology can be recognized as one of the most direct, effective, and rapid methods for sustainable organic synthesis, which has heralded a paradigm shift in chemical transformation as it shows some advantages like cleaner reactions, drastic acceleration of sluggish transformations, enhanced yields and improved selectivity, etc.4 The application of microwave irradiation has also unfolded new avenues in the traditionally challenging areas of the synthesis of heterocyclic compounds while circumventing the bottlenecks such as prolonged reaction time, low yields and formation of side products.5 For these reasons, microwave irradiation reactions can be promising from the viewpoint of sustainable and efficient chemical transformations. Due to their distinctive structural and electronic features, pyridones have been widely applied in pharmaceuticals, agrochemicals, materials and important synthetic intermediates (Figure 1).6−8 Heterocycles containing pyridone nucleus possess a variety of useful biological properties including antifungal, antiviral, cardiotonic, anti-inflammatory and anticancer © 2018 American Chemical Society

antiulcer agents ACE inhibitors and anti-HIV activities and so on.9 Such interesting biological applications have fascinated medicinal chemists worldwide who are continually seeking to develop new synthetic protocols to access pyridone-bearing pharmacophores.10−12 Over the last ten years, many powerful approaches have been developed for the construction of the pyridone moiety,13 including the classical Guareschi−Thorpe condensation,14 transition-metal-catalyzed reactions,15 directing-group-assisted intermolecular C−H annulation,16 and other methods17−19 have been emerging as powerful tools for the synthesis of this versatile molecule. However, there is an enormous need to explore new and highly efficient synthetic routes for this class of compounds and their functionalized derivatives, particularly those with advanced synthetic strategies and modern synthesis technology. On the other hand, domino reactions20 or multicomponent reactions (MCRs)21 known as cascade or tandem processes that involve simultaneous formation of multiple new C−C/ C−heteroatom bond and generate high levels of diversity and complexity under the same reaction conditions have become very attractive and highly desirable in organic synthesis.22 Consequently, it can be used for a multiplication effect to precisely splice complicated architectures from simple accessible materials atom-economically23 thus omitting the need for several Received: July 13, 2018 Published: September 19, 2018 12535

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry

Figure 1. Biologically active natural products and medicines containing 2-pyridone ring.

Scheme 1. Previous Work and This Novel Microwave Irradiation Domino Protocol

self-sorting branched domino reaction between two categories of dicarbonyl compounds, triethyl orthoformate as C1 building block, and amines under microwave irradiation and catalystand solvent-free conditions. In the process of reaction with cascade CN bond formation, CN bond changes to CN bond/CC bond formation, CC bond formation and CN bond formation (Scheme 1). These products containing pyridine rings are important precursors for the synthesis of some new pyridine-containing drugs and natural products.

workup and purification operations and allowing savings of both solvents and reagents.24 While at the same time minimizing chemical waste generation, step and atom economy and saving time are the advantages of these protocols.25 Recently, our group has developed a series of new MCRs that offer convenient and efficient access to some heterocycles of chemical and pharmaceutical under sustainable conditions.26−28 In continuation of our research, we disclose herein for the first time a novel one-pot four-component synthesis of a series of novel fully substituted 2-pyridone derivatives via 12536

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry Table 1. Screening Optimum Reaction Conditions for the Model Reactiona

entry

catalyst

solvent

temp (°C)

molar ratiob

time (h)

yield (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

CsCO3 Et3N CuO − − − − − − − − − − − − − − − −

DMF DMF DMF DMF Dioxane CH3CN EtOH Toluene DMSO H2O Ac2O − − − − − − − −

Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux Reflux 100 110 120 130 120 120 120 120

1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.0/1.0/1.0 1.0/1.2/1.0/1.0 1.0/1.2/1.2/1.0 1.0/1.2/1.4/1.0 1.0/1.2/1.4/1.1

3.0 4.0 3.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

20 12 Trace 42 28 35 30 36 42 N.R. 40 62 63 68 60 65 72 82 84

a

Reaction conditions unless stated otherwise: 1, 2, 3 and 4 in one-pot, catalysts (10% mmol). bMolar ratio of 1, 2, 3 and 4. cValues are the overall yields isolated product 5a, determined by 1H NMR, 13C NMR spectroscopy and HRMS.

■

RESULTS AND DISCUSSION Efficient and elegant synthesis would be an ideal testing ground to demonstrate the power and potential of this fourcomponent branched domino reaction. We commenced our study by investigating the reaction of methyl acetoacetate 1 (1.0 mmol), diethyl malonate 2 (1 mmol), triethyl orthoformate 3 (1.0 mmol), and aniline 4 (1.0 mmol) using CsCO3 as catalyst in N,N-dimethylformamide refluxing 3.0 h. The reaction furnished the desired 2-pyridine 5a in 20% yield (entry 1, Table 1). Following the promising results achieved with the above method, the reaction conditions, particularly, the change in catalysts, solvents, temperature and ratio, were investigated (entries 2−19). Initially, to search for the optimal catalysts, the microwave irradiation reaction was examined using Et3N, CuO as catalyst or catalyst-free conditions in N, N-dimethylformamide at reflux for 2.0−4.0 h (entries 1−4). Using Et3N as a catalyst, the conversion (12%) was very poor (entry 2). Only a trace amount of the product was observed when the reaction was carried out using CuO (entry 3). Surprisingly, when the mixture was conducted under catalystfree conditions, the product 5a was obtained in 42% yield and the reaction time could be reduced to 2.0 h (entry 4). Further screening of the reaction temperatures and various solvents showed that conducting the reaction under catalyst- and solventfree conditions at 100 °C gave better result (entries 4−12, entry 12). Among them dioxane, acetonitrile, ethanol, toluene, dimethyl sulfoxide and acetic anhydride were also as a solvents for this transformation in low yields, water failed to give the product (entry 10). Subsequently, investigating whether microwave heating temperature could further improve this conversion. The reaction was performed at different microwave temperatures to determine the optimum reaction condition.

The results showed that the best reaction microwave temperature was 120 °C (entry 14). The yield decreased slightly when the reaction was conducted at lower (100 °C) or higher temperatures (130 °C) (entries 12 and 15). Besides, screening of this reaction at different ratio of raw materials was also performed. It was quite evident that the increase in the quantities of 2 and the change in the optimal quantities of 3 led to formation of the target product in higher yield (entries 15−19, entry 19). On the basis of all of these experiments, the optimum reaction conditions were identified as follows: methyl acetoacetate 1 (1.0 mmol), diethyl malonate 2 (1.2 mmol), triethyl orthoformate 3 (1.4 mmol), and aniline 4 (1.1 mmol), without catalyst and solvent in one-pot reacted within 0.5 h at 120 °C under microwave irradiation (entry 19, Table 1). Having the optimal reaction conditions in hand (entry 19, Table 1), the scope of the reaction with respect to various anilines and readily available dicarbonyl compounds were then evaluated, and some results summarized in Table 2. Gratifyingly, reaction of aniline with electron-donating substituents (such as methyl, ethyl, methoxy, and t-Bu) at the para-position proceeded under the optimized reaction conditions in high yields 5f, 5g, 5h, 5i and 5j (entries 6−10), while the electronwithdrawing group on the same position aromatic ring also furnished the desired products 5b, 5c, 5d and 5e (entries 2−5), the yield was slightly lower. Moreover, the halogen substituent can be effectively compatible, and it is very important for further functionalization of pyridones 5b, 5c, 5s and 5t (entries 2, 3, 19 and 20). It is worth noting that 4-aminophenol did not generate the desired product 6h (entries 34). Subsequently, anilines with electron-withdrawing or electron-donating groups, such as halogen, methyl and methoxy at the meta-position reacted smoothly with diethyl malonate, triethyl orthoformate and dicarbonyl compound powder to give the corresponding 12537

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry Table 2. Substrate Scope of the Reaction for 2-Pyridones Using Anilines

12538

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry Table 2. continued

12539

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry Table 2. continued

Reaction conditions, unless stated otherwise: 1 (1.0 mmol), 2 (1.2 mmol), 3 (1.4 mmol) and 4 (1.1 mmol) in one-pot reacted at 120 °C under microwave irradiation and solvent and catalyst-free conditions. bIsolated yields based on 1.

a

products 5k, 5l and 5m in good yields (entries 11, 12 and 13). Similarly, ortho-substituted anilines were also successful in affording the corresponding pyridone products 5n, 5o and 5p (entries 14, 15 and 16) in moderate to excellent yields under the standard conditions. Therefore, the steric hindrance not be reduced the yields of pyridone products. To our delight, the reaction also worked well with 3-methyl-4-methoxyaniline, leading to the corresponding product 5q, 6g in 76%, 75% yield, respectively. Analysis of experimental results, either the electron-withdrawing group or the electron-donating group could be located at any position of the aniline, an electronwithdrawing group substituted on the aromatic ring disfavored the transformation with a marked decrease in the yield, but an electron-donating group substituted on the aromatic ring showed the opposite effect. Having described a microwave irradiation four component domino protocol under our optimized condition to diversityoriented construction of fully substituted 2-pyridones, as shown in Table 2, the reaction demonstrated a broad substrate scope readily forming a variety of 2-pyridones in satisfactory

yields. To further examine the scope and limitations of the reaction, the scope of various alkyl amines were also evaluated (entry 1−10, Table 3). The reaction elegantly occurred when methylamine, isopropylamine or 1-butylamine was used as the substrate, the products 7a, 7b, 7c, 7f, 7g and 7h were obtained in 58−68% yield. Besides, aminocyclopropane could also be used as substrate in this reaction (70% of 7d, 60% of 7i). Finally, the cyclohexylamine that was used as substrate could also obtain the corresponding pyridone 7e, 7j in 75% and 72% yields, respectively. The scope of the uncommon amines was our next concern. As shown in Table 4, various amine derivatives all afforded the target products in moderate to high yields under the optimized conditions (entries 1−6, Table 4). Benzylamine were first investigated, which could afford a moderate yield of the target 2-pyridone 8a (entry 1). In addition, other amines such as 1,1-diphenylmethylamine and furfurylamine could also react with methyl acetoacetate, diethyl malonate, and triethyl orthoformate to give the products 8b, 8d (entries 2, 4). Moreover, similar to the case the reaction of 12540

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry Table 3. Substrate Scope of the Reaction for 2-Pyridones Using Alkyl Amines

Reaction conditions, unless stated otherwise: 1 (1.0 mmol), 2 (1.2 mmol), 3 (1.4 mmol) and 4 (1.1 mmol) in one-pot reacted at 120 °C under microwave irradiation and solvent and catalyst-free conditions. bIsolated yields based on 1.

a

of imine-enamine tautomerization to obtain intermediate enamino ester C. Then, intermediate C reacted with diethyl ethoxymethylenemalonate A to form intermediate D via an aza-ene reaction mechanism and lost one molecular ethanol. Finally, intermediate D underwent an intramolecular cyclization followed by loss of ethanol to form the product pyridone.

1,1-diphenylmethylamine and furfurylamine could react with methyl acetoacetate, 2,4-pentanedione, and triethyl orthoformate, and a high yield of the product was obtained 8e, 8f (entry 5, 6). Finally, 1-aminonaphthalene could also be used as the substrate in this novel four components branched domino reaction (entry 3). On the basis of our experimental results and previous literatures,29 a tentative mechanism to account for the branched domino self-sorting system is proposed (Scheme 2). Initially, self-sorting behavior 1: Intermediate diethyl ethoxymethylenemalonate A was obtained through the condensation of diethyl malonate 1 and triethyl orthoformate 2. Selfsorting behavior 2: methyl acetoacetate 3 reacted with aniline 4 to form intermediate B, meanwhile B underwent a process

■

CONCLUSIONS In summary, we have disclosed a novel, simple, efficient and new route for the synthesis of a variety of 2-pyridone derivatives via a one-pot multicomponent reaction of two categories of dicarbonyl compounds, triethyl orthoformate and amines under microwave irradiation, sustainable and clean conditions. 12541

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry Table 4. Substrate Scope of the Reaction for 2-Pyridones Using Other Amines

Reaction conditions, unless stated otherwise: 1 (1.0 mmol), 2 (1.2 mmol), 3 (1.4 mmol) and 4 (1.1 mmol) in one-pot reacted at 120 °C under microwave irradiation and solvent and catalyst-free conditions. bIsolated yields based on 1.

a

Scheme 2. Postulated Self-Sorting Branched Domino Mechanism for the Formation of 2-Pyridone

The simple operation, moderate to excellent yields with fine substrate tolerance and sustainability of the present method make this method a valuable complementary tool in the synthesis of the novel pyridine-containing natural products and drugs. We believe that such efficient and clean methodologies could have great application potential to the optimization of synthetic procedures of pyridine. In addition, this series of

2-pyridones may prove new classes of biological active compound derivatives for biomedical screening, which is in progress in our laboratories.

■

EXPERIMENTAL SECTION

General Methods. All reagents were obtained from commercial suppliers and used without further purification. All compounds were characterized by full spectroscopic data. The 1H and 13C nuclear

12542

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry

C NMR (CDCl3, 100 MHz) δ 164.6, 164.5, 159.6, 157.9, 146.0, 141.3, 128.5, 127.3, 127.2, 117.8, 109.0, 61.5, 61.4, 20.4, 14.2. IR (KBr) (vmax, cm−1) 3454, 1717, 1658, 1532, 1441, 1322, 1232, 1192, 1065, 852, 579. HRMS (ESI-TOF) m/z Calcd for C18H16F3NNaO5+ [M + Na]+ 406.0873, found 406.0879. 3-Ethyl 5-methyl 6-methyl-1-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5e. Yield 39%, 140.52 mg; pale yellow solid; mp 116.1−116.8 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.83 (s, 1H, CH), 8.44 (d, J = 8.4 Hz, 2H, Ph-H), 7.39 (d, J = 8.8 Hz, 2H, Ph-H), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 3.90(s, 3H, OCH3), 2.45 (s, 3H, CH3), 1.35 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 164.5, 157.2, 148.2, 145.5, 129.6, 125.4, 124.1, 61.7, 53.6, 20.8, 14.2. IR (KBr) (vmax, cm−1) 3435, 2324, 1733, 1661, 1525, 1441, 1383, 1238, 1067, 1010, 863, 647, 548. HRMS (ESI-TOF) m/z Calcd for C17H17N2O7+ [M + H]+ 361.1030, found 361.1035. 3-Ethyl 5-methyl 6-methyl-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3,5-dicarboxylate 5f. Yield 79%, 260.18 mg; pale yellow solid; mp 158.2−162.4 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.81 (s, 1H, CH), 7.34 (d, J = 8.0 Hz, 2H, Ph-H), 7.02 (d, J = 7.6 Hz, 2H, Ph-H), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 3.88 (s, 3H, OCH3), 2.45 (s, 3H, CH3), 2.42 (s, 3H, CH3), 1.36 (t, J = 8.0 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 165.3, 159.2, 145.7, 139.4, 135.4, 130.7, 127.2, 117.3, 108.1, 61.4, 52.2, 21.2, 20.4, 14.2. IR (KBr) (vmax, cm−1) 3725, 1703, 1605, 1535, 1402, 1370, 1314, 1263, 1218, 1091, 1028, 863, 775, 614. HRMS (ESI-TOF) m/z Calcd for C18H19NNaO5+ [M + Na]+ 352.1155, found 352.1158. 3-Ethyl 5-methyl 1-(4-ethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5g. Yield 70%, 250.36 mg; pale yellow solid; mp 41.8−42.9 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.79 (s, 1H, CH), 7.35 (d, J = 8.4 Hz, 2H, Ph-H), 7.03 (d, J = 8.4 Hz, 2H, Ph-H), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 3.86 (s, 3H, OCH3), 2.72 (q, J = 7.6 Hz, 2H, CH2), 2.44 (s, 3H, CH3), 1.34 (t, J = 7.2 Hz, 3H, CH3), 1.27 (t, J = 7.6 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.3, 164.8, 159.8, 159.2, 145.6, 145.5, 135.6, 129.4, 127.2, 117.4, 108.1, 61.3, 52.1, 28.5, 20.4, 15.2, 14.2. IR (KBr) (vmax, cm−1) 3412, 1707, 1678, 1604, 1531, 1437, 1367, 1265, 1220, 1063, 862, 798, 774, 686, 549. HRMS (ESI-TOF) m/z Calcd for C19H22NO5+ [M + H]+ 344.1489, found 344.1492. 3-Ethyl 5-methyl 1-(4-isopropylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5h. Yield 75%, 268.05 mg; pale yellow solid; mp 162.1−163.7 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.79 (s, 1H, CH), 7.38 (d, J = 8.4 Hz, 2H, Ph-H), 7.04 (d, J = 8.4 Hz, 2H, Ph-H), 4.35 (q, J = 7.2 Hz, 2H, OCH2), 3.86 (s, 3H, OCH3), 2.98 (m, 1H, CH), 2.44 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3), 1.28−1.27 (m, 6H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.3, 164.9, 159.8, 159.2, 150.1, 145.6, 135.6, 128.0, 127.2, 117.4, 108.0, 61.3, 52.1, 33.8, 23.8, 20.4, 14.2. IR (KBr) (vmax, cm−1) 3412, 2959, 1698, 1677, 1602, 1581, 1427, 1371, 1314, 1258, 1220, 1033, 844, 800, 688, 571. HRMS (ESI-TOF) m/z Calcd for C20H24NO5+ [M + H]+ 358.1648, found 358.1649. 3-Ethyl 5-methyl 1-(4-(tert-butyl)phenyl)-6-methyl-2-oxo-1,2dihydropyridine-3,5-dicarboxylate 5i. Yield 68%, 252.57 mg; pale yellow solid; mp 189.1−191.2 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.79 (s, 1H, CH), 7.53 (d, J = 8.4 Hz, 2H, Ph-H), 7.05 (d, J = 8.4 Hz, 2H, Ph-H), 4.35 (q, J = 7.2 Hz, 2H, OCH2), 3.86 (s, 3H, OCH3), 2.44 (s, 3H, CH3), 1.36−1.33 (m, 12H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.3, 164.9, 159.8, 159.3, 152.4, 145.6, 135.3, 126.9, 117.4, 108.0, 61.3, 52.1, 34.8, 31.2, 20.4, 14.2. IR (KBr) (vmax, cm−1) 3414, 1705, 1432, 1272, 1029, 861, 774, 569. HRMS (ESI-TOF) m/z Calcd for C21H26NO5+ [M + H]+ 372.1803, found 372.1805. 3-Ethyl 5-methyl 1-(4-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5j. Yield 76%, 262.46 mg; pale yellow solid; mp 128.9−130 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.79 (s, 1H, CH), 7.03 (m, 4H, Ph-H), 4.36 (q, J = 8.0 Hz, 2H, OCH2), 3.87 (s, 3H, OCH3), 3.85(s, 3H, OCH3), 2.45 (s, 3H, CH3), 1.37 (t, J = 8.0 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.3, 159.9, 159.5, 145.7, 145.6, 130.6, 128.5, 117.3, 115.2, 108.5, 108.1, 61.4, 55.5, 20.5, 14.2. IR (KBr) (vmax, cm−1) 3451, 2983, 1700, 1607, 1510, 1441, 1369, 1315, 1260, 1216, 1144, 1091, 1027, 830, 775, 684, 13

magnetic resonance (NMR) spectra were recorded on a Bruker Avance III 400 MHz (1H NMR: 400 MHz, 13C NMR: 100 MHz) using CDCl3 or DMSO-d6 as solvent with TMS as internal standard. Chemical shifts are given in ppm (δ) referenced to CDCl3 with 7.26 for 1H and 77.16 for 13C, DMSO-d6 with 2.50 for 1H and 39.52 for 13 C. Signals are abbreviated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, and coupling constants are expressed in hertz. The melting points were determined on Tech X-5 melting point apparatus and are uncorrected. IR spectra (KBr pellet) were detected by a Thermo Nicolet S10 FT-IR instrument. HRMS were performed on an Agilent LC/MSD TOF instrument. All microwave reactions were performed in a commercially available multimode microwave reactor (CEM Discover-sp, CEM Corporation, North Carolina, USA), and the reaction temperature was maintained by an external infrared sensor (external surface sensor). General Experimental Procedure for the Synthesis of Pyridone. Methyl acetoacetate/2,4-pentanedione 1 (1.0 mmol), diethyl malonate 2 (1.2 mmol), triethyl orthoformate 3 (1.4 mmol) and amines 4 (1.1 mmol) were placed into a 5.0 mL microwave reaction tub (commercially available from CEM Corporation), closed the tube and stirred for 1 h at room temperature to make the raw materials mix well. The reaction mixture was subjected to irradiation in a sealed microwave reactor (CEM Discover-sp, CEM Corporation, North Carolina, USA) at 120 °C and 220 W initial power. The reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature. The mixture was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether = 1:20 (v/v)) to give the final product 2-pyridone derivatives. The products were further identified by FTIR, NMR and HRMS, being in good agreement with the assigned structures. Characterization and Spectroscopic Data of Pyridine 1−33, Table 2. 3-Ethyl 5-methyl 6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarboxylate 5a. Yield 84%, 264.87 mg; pale yellow solid; mp 111.2−111.7 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.80 (s, 1H, CH), 7.55−7.47 (m, 3H, Ph-H), 7.14 (d, J = 7.6 Hz, 2H, Ph-H), 4.35 (q, J = 7.2 Hz, 2H, OCH2), 3.86 (s, 3H, OCH3), 2.43 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.2, 164.7, 159.8, 158.9, 145.7, 138.1, 130.0, 129.3, 127.5, 117.5, 108.2, 61.4, 52.2, 21.2, 20.4, 14.2. IR (KBr) (vmax, cm−1) 3446, 1746, 1710, 1678, 1603, 1529, 1490, 1436, 1370, 1313, 1254, 1219, 1091, 863, 778, 708, 597. HRMS (ESI-TOF) m/z Calcd for C17H17NNaO5+ [M + Na]+ 338.0999, found 338.1002. 3-Ethyl 5-methyl 1-(4-bromophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5b. Yield 42%, 165.57 mg; pale yellow solid; mp 161.1−161.2 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.80 (s, 1H, CH), 7.68 (d, J = 8.4 Hz, 2H, Ph-H), 7.04 (d, J = 8.4 Hz, 2H, Ph-H), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 3.87(s, 3H, OCH3), 2.44 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.1, 164.5, 159.6, 158.5, 145.9, 137.0, 133.4, 129.3, 123.5, 117.6, 108.4, 61.5, 52.3, 20.4, 14.2. IR (KBr) (vmax, cm−1) 3454, 1705, 1603, 1533, 1485, 1429, 1365, 1314, 1264, 1213, 1124, 1067, 1025, 849, 775, 725, 580. HRMS (ESI-TOF) m/z Calcd for C17H16BrNNaO5+ [M + Na]+ 416.0104, found 416.0109. 3-Ethyl 5-methyl 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5c. Yield 69%, 229.98 mg; pale yellow solid; mp 105.3−105.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.78 (s, 1H, CH), 7.26−7.19 (m, 2H, Ph-H), 7.13−7.10 (m, 2H, Ph-H), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 2.43 (s, 3H, OCH3), 1.39 (t, J = 7.2 Hz, 3H, CH3), 1.35 (s, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 164.7, 163.9 (d, J = 76.2 Hz), 159.8, 158.6, 145.7, 133.9 (d, J = 3.5 Hz), 129.5 (d, J = 8.7 Hz),129.4, 117.2, 117.0, 108.7, 61.3, 20.4, 14.2. IR (KBr) (vmax, cm−1) 3410, 1708, 1606, 1508, 1442, 1267, 1031, 860, 571. HRMS (ESI-TOF) m/z Calcd for C17H17NFO5+ [M + H]+ 334.1088, found 334.1085. 3-Ethyl 5-methyl 6-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)1,2-dihydropyridine-3,5-dicarboxylate 5d. Yield 62%, 237.65 mg; pale yellow solid; mp 168.1−170.1 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.83 (s, 1H, CH), 7.84 (d, J = 8 Hz, 2H, Ph-H), 7.32 (d, J = 8 Hz, 2H, Ph-H), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 3.89(s, 3H, OCH3), 2.45 (s, 3H, CH3), 1.37 (t, J = 6.8 Hz, 3H, CH3). 12543

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry 562. HRMS (ESI-TOF) m/z Calcd for C18H20NO6+ [M + H]+ 346.1285, found 346.1293. 3-Ethyl 5-methyl 1-(3-bromophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5k. Yield 47%, 185.28 mg; pale yellow solid; mp 147.3−148.3 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.84 (s, 1H, CH), 8.44 (d, J = 8.4 Hz, 2H, Ph-H), 7.40 (d, J = 8.4 Hz, 2H, Ph-H), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 3.90(s, 3H, OCH3), 2.45 (s, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 164.7, 164.6, 159.6, 158.3, 146.0, 139.2, 132.6, 131.2, 130.9, 126.5, 123.4, 117.7, 108.8, 61.5, 61.4, 20.4, 14.3, 14.2. IR (KBr) (vmax, cm−1) 3405, 1705, 1579, 1533, 1438, 1357, 1254, 1032, 859, 796, 773, 676, 552. HRMS (ESI-TOF) m/z Calcd for C17H16BrNNaO5+ [M + Na]+ 416.0104, found 416.0110. 3-Ethyl 5-methyl 6-methyl-2-oxo-1-(m-tolyl)-1,2-dihydropyridine-3,5-dicarboxylate 5l. Yield 80%, 263.48 mg; pale yellow solid; mp 45.1−46.5 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.79 (s, 1H, CH), 7.42−7.26 (m, 2H, Ph-H), 6.94−6.91 (m, 2H, Ph-H), 4.34 (q, J = 7.2 Hz, 2H, OCH2), 2.44 (s, 3H, OCH3), 2.38 (s, 3H, CH3), 1.39 (t, J = 7.2 Hz, 3H, CH3), 1.33 (s, 3H, CH3),. 13 C NMR (CDCl3, 100 MHz) δ 164.9, 164.8, 159.8, 158.8, 145.7, 140.2, 138.1, 130.0, 129.8, 128.0, 124.4, 117.5, 108.5, 61.4, 61.2, 21.3, 20.4, 14.3, 14.2. IR (KBr) (vmax, cm−1) 3418, 2987, 1698, 1603, 1532, 1448, 1372, 1266, 1237, 1033, 861, 798, 775, 709, 574. HRMS (ESITOF) m/z Calcd for C18H20NO5+ [M + H]+ 330.1338, found 330.1336. 3-Ethyl 5-methyl 1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5m. Yield 71%, 245.20 mg; pale yellow solid; mp132.6−133.4 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.78 (s, 1H, CH), 7.43−7.26 (m, H, Ph-H), 7.00−6.97 (m, H, Ph-H), 6.71−6.64 (m, 2H, Ph-H), 4.33 (q, J = 7.2 Hz, 2H, OCH2), 3.85 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 2.45 (s, 3H, CH3), 1.33 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) 165.2, 164.7, 160.9, 159.7 159.0, 145.7, 139.0, 130.8, 119.5, 117.3, 115.2, 113.0, 108.1, 61.4, 55.4, 52.2, 29.6, 20.2, 14.2. IR (KBr) (vmax, cm−1) δ 3392, 2827, 1720, 1632, 1531, 1438, 1260, 1214, 1071, 860, 755, 560. HRMS (ESI-TOF) m/z Calcd for C18H20NO6+ [M + H]+ 346.1291, found 346.1294. 3-Ethyl 5-methyl 6-methyl-2-oxo-1-(o-tolyl)-1,2-dihydropyridine-3,5-dicarboxylate 5n. Yield 76%, 250.30 mg; pale yellow solid; mp 134.8−137 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.84 (s, 1H, CH), 7.38−7.35 (m, 3H, Ph-H), 7.04−7.02 (m, 1H, Ph-H), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 3.89 (s, 3H, OCH3), 2.40 (s, 3H, CH3), 2.06 (s, 3H, CH3), 1.41−1.35 (t, J = 7.6 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 165.2, 164.7, 159.1, 158.9, 145.8, 137.3 134.7, 131.5, 129.5, 127.7, 117.4, 108.1, 61.4, 52.2, 19.6, 17.2, 14.2. IR (KBr) (vmax, cm−1) 3785, 3382, 2315, 1696, 1438, 1261, 1068, 1023, 861, 549. HRMS (ESI-TOF) m/z Calcd for C18H19NNaO5+ [M + Na]+ 352.1155, found 352.1157. 3-Ethyl 5-methyl 1-(2-isopropylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5o. Yield 50%, 178.70 mg; pale yellow solid; mp 49.1−50.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.79 (s, 1H, CH), 7.47−7.45 (m, 2H, Ph-H), 7.33−6.96 (m, 2H, Ph-H), 4.35 (q, J = 7.2 Hz, 2H, OCH2), 3.87 (s, 3H, OCH3), 2.51−2.44 (m, 1H, CH), 2.39 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3), 1.17−1.14 (m, 6H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.3, 164.7, 159.3, 159.1, 145.4, 145.1, 135.8, 129.9, 127.4, 127.3, 117.6, 107.8, 61.3, 52.1, 28.2, 24.0, 23.1, 20.1, 14.2. IR (KBr) (vmax, cm−1) 3400, 2963, 2960, 1698, 1680, 1599, 1528, 1488, 1434, 1371, 1255, 1227, 1033, 860, 762, 687, 570. HRMS (ESI-TOF) m/z Calcd for C20H24NO5+ [M + H]+ 358.1646, found 358.1649. 3-Ethyl 5-methyl 1-(2-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 5p. Yield 75%, 259.01 mg; pale yellow solid; mp 134.7−139.5 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.79 (s, 1H, CH), 7.41 (m, 1H, Ph-H), 7.06−7.01 (m, 3H, Ph-H), 4.33 (q, J = 7.2 Hz, 2H, OCH2), 3.84 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 2.40 (s, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.3, 164.8, 159.9, 159.3, 154.0, 145.8, 130.9, 128.7, 126.5, 121.3, 117.1, 112.1, 107.9, 61.2, 55.7, 52.1, 19.3, 14.2. IR (KBr) (vmax, cm−1) 3430, 2925, 1713, 1602, 1531, 1438, 1320, 1260, 1071, 860, 802, 755, 573. HRMS (ESI-TOF) m/z Calcd for C18H19NNaO6+ [M + Na]+ 368.1105, found 368.1109.

3-Ethyl 5-methyl 1-(4-methoxy-3-methylphenyl)-6-methyl-2-oxo1,2-dihydropyridine-3,5-dicarboxylate 5q. Yield 76%, 272.94 mg; pale yellow solid; mp 108.2−110.8 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.78 (s, 1H, CH), 6.92−6.88 (m, 3H, Ph-H), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 3.87 (s, 6H, OCH3), 2.47 (s, 3H, CH3), 2.22 (s, 3H, CH3), 1.36 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.3, 164.9, 159.6, 158.1, 145.5, 130.1, 129.2, 128.8, 125.6, 117.4, 110.7, 108.0, 61.3, 55.5, 52.1, 20.4, 16.3, 14.2. IR (KBr) (vmax, cm−1) 3450, 2579, 1720, 1607, 1514, 1441, 1395, 1315, 1270, 1206, 1091, 1027, 830, 785, 684, 560. HRMS (ESI-TOF) m/z Calcd for C19H22NO6+ [M + H]+ 360.1447, found 360.1448. Ethyl 5-acetyl-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3carboxylate 5r. Yield 75%, 224.49 mg; pale yellow solid; mp 113.2−115.5 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.70 (s, 1H, CH), 7.56−7.49 (m, 3H, Ph-H), 7.15−7.13 (m, 2H, Ph-H), 4.39 (q, J = 6.8 Hz, 2H, OCH2), 2.59 (s, 3H, CH3), 2.38 (s, 3H, CH3), 1.37 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.3, 165.0, 159.4, 158.7, 145.3, 138.0, 130.1, 129.3, 127.4, 116.7, 116.2, 61.6, 29.3, 20.8, 14.2. IR (KBr) (vmax, cm−1) 3404, 2386, 2026, 1667, 1588, 1441, 1361, 1262, 1071, 860, 794, 689, 548. HRMS (ESI-TOF) m/z Calcd for C17H17NNaO4+ [M + Na]+ 322.1050, found 322.1049. Ethyl 5-acetyl-1-(4-bromophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 5s. Yield 37%, 139.94 mg; pale yellow solid; mp 173.2−181.3 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.69 (s, 1H, CH), 7.69 (d, J = 7.6 Hz, 2H, Ph-H), 7.03 (d, J = 8.4 Hz, 2H, Ph-H), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 2.58 (s, 3H, CH3), 2.39 (s, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 195.1, 163.7, 158.2, 157.2, 144.3, 135.9, 132.3, 128.2, 122.6, 115.9, 115.3, 60.6, 30.9, 28.6, 21.6, 13.0. IR (KBr) (vmax, cm−1) 3407, 1701, 1666, 1587, 1519, 1440, 1378, 1261, 1224, 1040, 863, 797, 573. HRMS (ESI-TOF) m/z Calcd for C17H16BrNNaO4+ [M + Na]+ 400.0155, found 400.0159. Ethyl 5-acetyl-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 5t. Yield 66%, 209.43 mg; pale yellow solid; mp 111.9−112.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.67 (s, 1H, CH), 7.24−7.20 (m, 2H, Ph-H), 7.13−7.09 (m, 2H, Ph-H), 4.37 (q, J = 7.2 Hz, 2H, OCH2), 2.56 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.39 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 195.2, 163.8, 160.5, 158.4, 157.5, 144.3, 132.8 (d, J = 3.5 Hz), 132.7, 128.4 (d, J = 8.7 Hz), 128.3, 116.3, 116.3 (d, J = 23.0 Hz), 115.3 60.6, 28.3, 19.8, 13.2. IR (KBr) (vmax, cm−1) 3410, 3074, 2985, 1710, 1661, 1587, 1504, 1441, 1374, 1258, 1136, 1021, 953, 846, 796, 590, 544. HRMS (ESI-TOF) m/z Calcd for C17H17NFO4+ [M + H]+ 318.1132, found 318.1136. Ethyl 5-acetyl-6-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)-1, 2-dihydropyridine-3-carboxylate 5u. Yield 79%, 290.18 mg; pale white solid; mp 195.4−197.4 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.71 (s, 1H, CH), 7.84 (d, J = 8 Hz, 2H, Ph-H), 7.31 (d, J = 7.6 Hz, 2H, Ph-H), 4.39 (q, J = 6.8 Hz, 2H, OCH2), 2.60(s, 3H, CH3), 2.38 (s, 3H, CH3), 1.37 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.1, 164.6, 159.1, 157.8, 145.5, 141.4, 128.4, 127.3, 117.1, 116.5, 61.7, 29.3, 20.8, 14.2. IR (KBr) (vmax, cm−1) 3130, 2301, 1667, 1441, 1380, 1325, 1263, 1122, 1066, 1010, 863, 797, 739, 549. HRMS (ESI-TOF) m/z Calcd for C18H16F3NNaO4+ [M + Na]+ 390.0924, found 390.0926. Ethyl 5-acetyl-6-methyl-1-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 5v. Yield 40%, 137.73 mg; pale yellow solid; mp 192.5−194.7 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.72 (s, 1H, CH), 8.44 (d, J = 8.8 Hz, 2H, Ph-H), 7.39 (d, J = 8.4 Hz, 2H, Ph-H), 4.40 (q, J = 7.2 Hz, 2H, OCH2), 2.60 (s, 3H, CH3), 2.38 (s, 3H, CH3), 1.38 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.0, 164.4, 157.2, 148.2, 145.5, 143.5, 129.2, 125.4, 117.3, 116.7, 61.8, 29.4, 20.8, 14.2. IR (KBr) (vmax, cm−1) 3378, 2300, 1698, 1662, 1592, 1527, 1441, 1351, 1261, 1120, 1067, 1009, 862, 738, 549. HRMS (ESI-TOF) m/z Calcd for C17H16N2NaO6+ [M + Na]+ 367.0901, found 367.0909. Ethyl 5-acetyl-6-methyl-2-oxo-1-(p-tolyl)-1,2-dihydropyridine-3carboxylate 5w. Yield 77%, 241.28 mg; pale yellow solid; mp 148. 1−150.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.69 (s, 1H, CH), 7.34 (d, J = 7.2 Hz, 2H, Ph-H), 7.02 (d, J = 7.6 Hz, 2H, Ph-H), 4.38 12544

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry

CH3), 2.42 (s, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.2, 165.0, 160.9, 159.3, 158.7, 145.3, 139.0, 130.8, 119.5, 116.1, 115.2, 113.1, 61.6, 55.4, 29.3, 20.7, 14.2. IR (KBr) (vmax, cm−1) 3379, 2310, 1679, 1654, 1593, 1502, 1436, 1237, 1217, 1067, 866, 762, 551. HRMS (ESI-TOF) m/z Calcd for C18H20NO5+ [M + H]+ 330.1336, found 330.1337. Ethyl 5-acetyl-6-methyl-2-oxo-1-(o-tolyl)-1,2-dihydropyridine-3carboxylate 6d. Yield 76%, 238.14 mg; pale yellow solid; mp 129.9−131.3 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.73 (s, 1H, CH), 7.38−7.35 (m, 3H, Ph-H), 7.03−7.01 (m, 1H, Ph-H), 4.39 (q, J = 6.8 Hz, 2H, OCH2), 2.59 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.05 (s, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.2, 165.0, 158.7, 145.4, 137.2, 134.6, 131.6, 129.6, 127.7, 127.2, 116.7, 116.1, 61.6, 29.3, 20.0, 17.2, 14.2. IR (KBr) (vmax, cm−1) 3130, 2987, 2317, 1704, 1662, 1584, 1511, 1444, 1374, 1255, 1219, 1138, 1037, 862, 798, 742, 548. HRMS (ESI-TOF) m/z Calcd for C18H19NNaO4+ [M + Na]+ 336.1206, found 336.1205. Ethyl 5-acetyl-1-(2-isopropylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 6e. Yield 59%, 201.43 mg; pale yellow solid; mp 171.9−173.1 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.68 (s, 1H, CH), 7.49−7.43 (m, 2H, Ph-H), 7.33−6.95 (m, 2H, Ph-H), 4.37 (q, J = 7.2 Hz, 2H, OCH2), 2.58 (s, 3H, CH3), 2.50−2.43 (m, 1H, CH), 2.34 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3), 1.17−1.14 (m, 6H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.1, 165.0, 159.0, 145.1, 135.7, 129.9, 127.4, 127.3, 116.8, 115.7, 61.4, 29.3, 28.2, 24.0, 23.1, 20.6, 14.2. IR (KBr) (vmax, cm−1) 3403, 2994, 2960, 1700, 1664, 1588, 1509, 1486, 1449, 1376, 1310, 1257, 1222, 1032, 950, 862, 761, 706, 558. HRMS (ESI-TOF) m/z Calcd for C20H24NO4+ [M + H]+ 342.1696, found 342.1700. Ethyl 5-acetyl-1-(2-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 6f. Yield 75%, 247.01 mg; pale yellow solid; mp 177.5−178.7 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.71 (s, 1H, CH), 7.47−7.43 (m, 1H, Ph-H), 7.09−7.04 (m, 3H, Ph-H),4.38 (q, J = 6.8 Hz, 2H, OCH2), 3.77 (s, 3H, OCH3), 2.58 (s, 3H, CH3), 2.38 (s, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 196.3, 165.1, 159.7, 158.9, 153.9, 145.5, 130.9, 128.6, 126.4, 121.4, 116.4, 115.9, 112.1, 61.5, 55.7, 29.3, 19.7, 14.3. IR (KBr) (vmax, cm−1) 3381, 2319, 1698, 1665, 1593, 1502, 1442, 1375, 1262, 1217, 1067, 862, 741, 548. HRMS (ESI-TOF) m/z Calcd for C18H19NNaO5+ [M + Na]+ 352.1155, found 352.1157. Ethyl 5-acetyl-1-(4-methoxy-3-methylphenyl)-6-methyl-2-oxo1,2-dihydropyridine-3-carboxylate 6g. Yield 75%, 257.53 mg; pale yellow solid; mp 126.1−127.2 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.68 (s, 1H, CH), 6.92−6.88 (m, 3H, Ph-H), 4.37 (q, J = 7.2 Hz, 2H, OCH2), 3.87 (s, 3H, OCH3), 2.57 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.36 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 196.4, 165.2, 159.8, 158.1, 145.3, 129.9, 129.1, 128.8, 125.5, 116.4, 116.1, 110.7, 61.6, 55.5, 29.4, 21.0, 16.3, 14.2. IR (KBr) (vmax, cm−1) 3376, 2041, 1789, 1662, 1576, 1506, 1420, 1272, 1209, 1069, 1022, 853, 796, 557. HRMS (ESI-TOF) m/z Calcd for C19H22NO5+ [M + H]+ 344.1498, found 344.1499. Characterization and Spectroscopic Data of Pyridine 1−10, Table 3. 3-Ethyl 5-methyl 1,6-dimethyl-2-oxo-1,2-dihydropyridine3,5-dicarboxylate 7a. Yield 65%, 164.61 mg; pale yellow solid; mp 100.8−102.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.67 (s, 1H, CH), 4.73 (s, 1H, NCH), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 3.86 (s, 3H, OCH3), 3.64 (s, 3H, NCH3) 2.85 (s, 3H, CH3), 1.38 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.4, 164.7, 159.6, 158.3, 144.4, 116.3, 108.2, 61.3, 52.2, 32.1, 18.6, 14.3. IR (KBr) (vmax, cm−1) 3419, 2026, 1662, 1601, 1587, 1523, 1442, 1371, 1252, 1059, 860, 549. HRMS (ESI-TOF) m/z Calcd for C12H15NNaO5+ [M + Na]+ 276.0842, found 276.0844. 3-Ethyl 5-methyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 7b. Yield 68%, 191.29 mg; pale white solid; mp 144−148.4 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.55 (s, 1H, CH), 4.73 (s, 1H, NCH), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 3.83 (s, 3H, OCH3), 2.82 (s, 3H, CH3), 1.68−1.62 (m, 6H, CH3, CH3). 13 C NMR (CDCl3, 100 MHz) δ 165.9, 164.6, 159.9, 144.1, 108.6, 61.2, 52.2, 19.5, 18.4, 14.3. IR (KBr) (vmax, cm−1) 3406, 1697, 1669, 1603, 1534, 1431, 1361, 1299, 1253, 1030, 860, 801, 775, 550. HRMS

(q, J = 6.8 Hz, 2H, OCH2), 2.58 (s, 3H, CH3), 2.42 (s, 3H, CH3), 2.39 (s, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.3, 165.0, 159.5, 158.9, 145.2, 139.4, 135.3, 130.7, 127.1, 116.6, 116.1, 61.5, 29.3, 21.2, 20.9, 14.2. IR (KBr) (vmax, cm−1) 3385, 1709, 1668, 1588, 1504, 1440, 1371, 1262, 1070, 862, 733, 549. HRMS (ESI-TOF) m/z Calcd for C18H19NNaO4+ [M + Na]+ 336.1206, found 336.1208. Ethyl 5-acetyl-1-(4-ethylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 5x. Yield 70%, 229.16 mg; pale yellow solid; mp 183.1−184.3 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.68 (s, 1H, CH), 7.35 (d, J = 8.4 Hz, 2H, Ph-H), 7.03 (d, J = 8.4 Hz, 2H, Ph-H), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 2.72 (q, J = 7.6 Hz, 2H, CH2), 2.57 (s, 3H, CH3), 2.38 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3), 1.26 (t, J = 7.6 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.3, 165.1, 159.5, 158.9, 145.5, 145.2, 135.4, 129.5, 127.1, 116.6, 116.1, 61.5, 29.3, 28.5, 20.9, 15.2, 14.2. IR (KBr) (vmax, cm−1) 3412, 2960, 1704, 1664, 1589, 1503, 1453, 1374, 1297, 1254, 1216, 1053, 866,796, 695, 649, 572, 554. HRMS (ESI-TOF) m/z Calcd for C19H22NO4+ [M + H]+ 328.1539, found 328.1543. Ethyl 5-acetyl-1-(4-isopropylphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 5y. Yield 60%, 204.84 mg; pale yellow solid; mp 181.5−182.2 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.68 (s, 1H, CH), 7.38 (d, J = 8.4 Hz, 2H, Ph-H), 7.03 (d, J = 8.4 Hz, 2H, Ph-H), 4.37 (q, J = 7.2 Hz, 2H, OCH2), 2.98 (m, 1H, CH), 2.57 (s, 3H, CH3), 2.38 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3), 1.28−1.26 (m, 6H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.3, 165.1, 159.5, 159.0, 150.1, 145.2, 135.5, 128.0, 127.1, 126.8, 116.6, 116.1, 61.5, 33.8, 31.2, 29.3, 23.8, 20.9, 14.2. IR (KBr) (vmax, cm−1) 3413, 2958, 1701, 1663, 1587, 1500, 1442, 1373, 1252, 1218, 1029, 866, 796, 570. HRMS (ESI-TOF) m/z Calcd for C20H24NO4+ [M + H]+ 342.1695, found 342.1700. Ethyl 5-acetyl-1-(4-(tert-butyl)phenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 5z. Yield 76%, 270.13 mg; pale yellow solid; mp 78.1−79.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.68 (s, 1H, CH), 7.53 (d, J = 8.8 Hz, 2H, Ph-H), 7.04 (d, J = 8.8 Hz, 2H, Ph-H), 4.36 (q, J = 7.2 Hz, 2H, OCH2), 2.57 (s, 3H, CH3), 2.38 (s, 3H, CH3), 1.37−1.33 (m, 12H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.3, 165.1, 159.5, 159.0, 152.4, 145.2, 135.2, 127.0, 126.8, 116.6, 116.1, 61.5, 34.8, 31.2, 29.3, 20.9, 14.2. IR (KBr) (vmax, cm−1) 3413, 2965, 1701, 1664, 1588, 1502, 1443, 1373, 1256, 1217, 1029, 866, 795, 571. HRMS (ESI-TOF) m/z Calcd for C21H26NO4+ [M + H]+ 356.1851, found 356.1856. Ethyl 5-acetyl-1-(4-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 6a. Yield 80%, 263.48 mg; pale yellow solid; mp 179.7−180.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.68 (s, 1H, CH), 7.03 (m, 4H, Ph-H), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 3.85 (s, 3H, OCH3), 2.58 (s, 3H, CH3), 2.40 (s, 3H, CH3), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.3, 165.0, 160.0, 159.7, 159.2, 145.2, 130.4, 116.6, 116.1, 115.3, 61.5, 55.5, 29.3, 20.9, 14.2. IR (KBr) (vmax, cm−1) 3383, 2026, 1702, 1664, 1588, 1506, 1439, 1376, 1257, 1219, 1069, 1031, 863, 796, 550. HRMS (ESI-TOF) m/z Calcd for C18H19NNaO5+ [M + Na]+ 352.1155, found 352.1158. Ethyl 5-acetyl-1-(3-bromophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 6b. Yield 35%, 132.38 mg; pale yellow solid; mp 118.9−126.3 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.68 (s, 1H, CH), 7.64 (m, H, Ph-H), 7.42 (m, H, Ph-H), 7.33 (m, H, Ph-H) 7.10 (m, H, Ph-H) 4.38 (q, J = 7.2 Hz, 2H, OCH2), 2.57 (s, 3H, CH3), 2.39 (s, 3H, CH3) 1.36 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 196.1, 164.7, 159.2, 158.1, 145.4, 139.0, 132.7, 131.2, 130.8, 126.3, 123.5, 116.9, 116.4, 61.7, 29.3, 20.8, 14.2. IR (KBr) (vmax, cm−1) 3402, 1704, 1663, 1587, 1509, 1440, 1376, 1253, 1219, 1039, 862, 797, 741, 671, 572, 550. HRMS (ESI-TOF) m/z Calcd for C17H16BrNNaO4+ [M + Na]+ 400.0155, found 400.0162. Ethyl 5-acetyl-1-(3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 6c. Yield 71%, 233.84 mg; pale yellow solid; mp 178.2−179.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.69 (s, 1H, CH), 7.46−7.00 (m, 2H, Ph-H), 6.73−6.65 (m, 2H, Ph-H), 4.38 (q, J = 7.2 Hz, 2H, OCH2), 3.81 (s, 3H, OCH3), 2.58 (s, 3H, 12545

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry

11.2. IR (KBr) (vmax, cm−1) 3388, 1667, 1585, 1523, 1443, 1259, 1070, 860, 549. HRMS (ESI-TOF) m/z Calcd for C14H17NNaO4+ [M + Na]+ 286.1050, found 286.1052. Ethyl 5-acetyl-1-cyclohexyl-6-methyl-2-oxo-1,2-dihydropyridine3-carboxylate 7j. Yield 72%, 219.87 mg; pale yellow solid; mp 126.1−127.4 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.42 (s, 1H, CH), 4.39 (m, 2H, OCH2), 2.74 (s, 3H, CH3), 2.52 (s, 3H, CH3), 1.89−1.88(m, 4H, CH2), 1.66 (s, 1H, NCH3), 1.39−1.37 (m, 9H, CH2CH3). 13C NMR (CDCl3, 100 MHz) δ 197.1, 164.9, 159.7, 143.4, 117.0, 61.3, 29.5, 26.4, 24.9, 14.3. IR (KBr) (vmax, cm−1) 3138, 1697, 1663, 1590, 1448, 1294, 1242, 1035, 862, 797, 740, 550. HRMS (ESI-TOF) m/z Calcd for C17H24NO4+ [M + H]+ 306.1692, found 306.1700. Characterization and Spectroscopic Data of Pyridine 1−6, Table 4. 3-Ethyl 5-methyl 1-benzyl-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 8a. Yield 63%, 207.49 mg; pale yellow solid; mp 115.4−116.8 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.73 (s, 1H, CH), 7.33−7.28 (m, 3H, Ph-H), 7.15−7.13 (d, 2H, Ph-H), 5.48 (s, 2H, NCH2), 4.42 (q, J = 7.0 Hz, 2H, OCH2), 3.85 (s, 3H, OCH3), 2.78 (s, 3H, CH3), 1.40 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.4, 164.6, 159.7, 158.8, 145.0, 135.0, 128.9, 127.7, 126.4, 126.8, 116.8, 108.6, 61.4, 52.3, 48.1, 18.4, 14.3. IR (KBr) (vmax, cm−1) 3379, 2315, 1707, 1528, 1369, 1241, 1068, 862, 740, 547. HRMS (ESI-TOF) m/z Calcd for C18H20NO5+ [M + H]+ 330.1336, found 330.1332. 3-Ethyl 5-methyl 1-benzhydryl-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 8b. Yield 55%, 222.99 mg; pale yellow solid; mp 135.4−136.9 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.75 (s, 1H, CH), 8.25 (s, 1H, NCH), 7.36−7.30 (m, 6H, Ph-H), 7.22−7.21 (m, 4H, Ph-H), 4.39 (q, J = 6.4 Hz, 2H, OCH2), 3.83(s, 3H, OCH3), 2.44 (s, 3H, CH3), 1.38 (t, J = 6.8 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 165.2, 164.6, 160.3, 159.9, 145.0, 137.0, 128.6, 127.9, 127.6, 116.9, 109.1, 61.4, 52.2, 22.0, 14.3, 14.2. IR (KBr) (vmax, cm−1) 3419, 2986, 1698, 1671, 1602, 1524, 1440, 1373, 1248, 1143, 1029, 861, 800, 777, 698, 581. HRMS (ESI-TOF) m/z Calcd for C24H23NNaO5+ [M + Na]+ 428.1468, found 428.1463. 3-Ethyl 5-methyl 6-methyl-1-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 8c. Yield 52%, 190.00 mg; pale yellow solid; mp 113.9−116.7 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.93 (s, 1H, CH), 7.96−7.90 (m, 2H, Ph-H), 7.58−7.44 (m, 3H, Ph-H), 7.32−7.26 (m, 2H, Ph-H), 4.37 (q, J = 7.2 Hz, 2H, OCH2), 3.90 (s, 3H, OCH3), 2.36 (s, 3H, CH3), 1.34 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 165.2, 164.8, 159.8, 159.7, 146.0, 134.7, 134.5, 129.9, 128.7, 128.0, 126.9, 125.7, 125.6, 121.2, 117.6, 108.4, 61.5, 52.2, 19.6, 14.2. IR (KBr) (vmax, cm−1) 3411, 1699, 1677, 1604, 1532, 1438, 1370, 1313, 1255, 1231, 1042, 861, 802, 778, 737, 550. HRMS (ESI-TOF) m/z Calcd for C21H19NNaO5+ [M + Na]+ 388.1155, found 388.1163. 3-Ethyl 5-methyl 1-(furan-2-ylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 8d. Yield 78%, 249.06 mg; white yellow solid; mp 98.2−99.6 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.47 (s, 1H, CH), 7.26−7.21 (m, 1H, CH), 6.40−6.25 (m, 2H, CH), 5.31 (s, 2H, NCH2), 4.33 (q, J = 7.2 Hz, 2H, OCH2), 2.88 (s, 3H, CH3), 2.47 (s, 3H, CH3), 1.32 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (CDCl3, 100 MHz) δ 195.6, 163.6, 157.7, 158.9, 156.9, 147.3, 143.2, 141.3, 115.7, 115.0, 109.7, 109.4, 60.4, 40.2, 28.4, 17.5, 13.3. IR (KBr) (vmax, cm−1) 3145, 3123, 2989, 1713, 1662, 1589, 1521, 1439, 1380, 1247, 1028, 860, 802, 778, 569. HRMS (ESI-TOF) m/z Calcd for C16H18NO6+ [M + H]+ 320.1125, found 320.1129. Ethyl 5-acetyl-1-benzhydryl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 8e. Yield 50%, 194.72 mg; pale yellow solid; mp 158.3−161.7 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 11.69 (s, 1H, NCH), 8.69 (s, 1H, CH), 7.26 (m, 10H, Ph-H), 4.42 (q, J = 7.2 Hz, 2H, OCH2), 2.77(s, 3H, OCH3), 2.54 (s, 3H, CH3), 1.41 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 195.1, 164.2, 161.7, 158.1, 147.0, 116.2, 61.4, 28.6, 20.8, 14.2. IR (KBr) (vmax, cm−1) 3383, 1696, 1652, 1583, 1445, 1366, 1245, 1070, 1007, 861, 800, 741, 547. HRMS (ESI-TOF) m/z Calcd for C24H24NO4+ [M + H]+ 390.1700, found 390.1707.

(ESI-TOF) m/z Calcd for C14H19NNaO5+ [M + Na]+ 304.1155, found 304.1160. 3-Ethyl 5-methyl 1-butyl-6-methyl-2-oxo-1,2-dihydropyridine3,5-dicarboxylate 7c. Yield 62%, 183.11 mg; viscous liquid; 1 H NMR (CDCl3, 400 MHz, TMS) δ 8.59 (s, 1H, CH), 4.32 (q, J = 6.8 Hz, 2H, OCH2), 4.08 (s, 2H, NCH2) 3.80 (s, 3H, OCH3), 2.81 (s, 3H, CH3) 1.62 (s, 2H, CH2), 1.34 (m, 5H, CH2, CH3) 0.91 (m, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 165.4, 164.7, 159.2, 157.8, 144.4, 116.3, 108.2, 61.2, 52.1, 45.3, 30.0, 20.2, 17.9, 14.3, 13.5. IR (KBr) (vmax, cm−1) 3435, 2961, 1715, 1668, 1603, 1536, 1436, 1370, 1300, 1232, 1148, 1069, 1033, 959, 861, 804, 778, 685, 547. HRMS (ESI-TOF) m/z Calcd for C15H21NNaO5+ [M + Na]+ 318.1312, found 318.1317. 3-Ethyl 5-methyl 1-cyclopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 7d. Yield 70%, 195.50 mg; pale white solid; mp 122.8−124.4 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.61 (s, 1H, CH), 4.37 (q, J = 7.2 Hz, 2H, OCH2), 3.85 (s, 3H, OCH3), 2.92 (m, 4H, NCH, CH3), 1.37 (t, J = 6.8 Hz, 3H, CH3), 0.84 (m, 4H, 2 CH2). 13C NMR (CDCl3, 100 MHz) δ 165.3, 164.6, 161.2, 160.7, 144.2, 117.2, 108.1, 61.2, 52.0, 29.7, 19.5, 14.3, 11.2. IR (KBr) (vmax, cm−1) 3403, 1736, 1708, 1662, 1599, 1533, 1433, 1311, 1223, 1132, 1037, 861, 779, 571. HRMS (ESI-TOF) m/z Calcd for C14H17NNaO5+ [M + Na]+ 302.0999, found 302.1003. 3-Ethyl 5-methyl 1-cyclohexyl-6-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate 7e. Yield 75%, 241.03 mg; pale yellow solid; mp 155.9−156.5 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.54 (s, 1H, CH), 4.35 (q, J = 7.2 Hz, 2H, OCH2), 3.83 (s, 3H, OCH3), 2.81 (s, 3H, CH3), 1.88−1.86(m, 4H, CH2), 1.65 (s, 1H, NCH), 1.37−1.33 (m, 7H, CH2CH3). 13C NMR (CDCl3, 100 MHz) δ 165.9, 164.7, 160.1, 144.0, 108.7, 61.2, 52.2, 28.0, 26.5, 25.0, 14.4. IR (KBr) (vmax, cm−1) 3394, 1696, 1575, 1536, 1441, 1366, 1242, 1035, 861, 800, 548. HRMS (ESI-TOF) m/z Calcd for C17H24NO5+ [M + H]+ 322.1644, found 322.1649. Ethyl 5-acetyl-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate 7f. Yield 62%, 147.10 mg; pale yellow solid; mp 93.4−95.3 °C. 1 H NMR (CDCl3, 400 MHz, TMS) δ 8.55 (s, 1H, CH), 4.40 (q, J = 7.2 Hz, 2H, OCH2), 3.64 (s, 3H, NCH3), 2.77 (s, 3H, CH3) 2.54 (s, 3H, CH3), 1.40 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.5, 164.9, 159.2, 158.0, 143.9, 116.4, 115.5, 61.4, 32.1, 29.3, 18.9, 14.3. IR (KBr) (vmax, cm−1) 3386, 2321, 1734, 1703, 1659, 1590, 1521, 1427, 1371, 1305, 1254, 1223, 1113, 1023, 865, 796, 739, 655, 550. HRMS (ESI-TOF) m/z Calcd for C12H15NNaO4+ [M + Na]+ 260.0893, found 260.0894. Ethyl 5-acetyl-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine3-carboxylate 7g. Yield 58%, 153.88 mg; pale white solid; mp 133.4−133.7 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.45 (s, 1H, CH), 4.40 (q, J = 6.8 Hz, 2H, OCH2), 2.75 (s, 3H, CH3) 2.53 (s, 3H, CH3), 1.65−1.63 (m, 6H, 2CH3), 1.39 (t, J = 6.8 Hz, 3H, CH3), 1.25(s, 1H, NCH). 13C NMR (CDCl3, 100 MHz) δ 197.1, 164.8, 159.5, 143.5, 116.9, 61.3, 29.6, 19.5, 18.8, 14.3. IR (KBr) (vmax, cm−1) 3407, 2026, 1659, 1587, 1519, 1442, 1378, 1245, 1071, 860, 549. HRMS (ESI-TOF) m/z Calcd for C14H19NNaO4+ [M + Na]+ 288.1206, found 288.1210. Ethyl 5-acetyl-1-butyl-6-methyl-2-oxo-1,2-dihydropyridine-3carboxylate 7h. Yield 58%, 162.01 mg; viscous liquid; 1H NMR (CDCl3, 400 MHz, TMS) δ 8.47 (s, 1H, CH), 4.33 (m, 2H, OCH2), 4.08 (s, 2H, NCH2) 2.73 (s, 3H, CH3), 2.48 (s, 3H, CH3) 1.61 (s, 2H, CH2), 1.36 (m, 5H, CH2, CH3) 0.91 (m, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 196.6, 164.9, 158.8, 157.5, 144.0, 129.7, 117.1, 116.4, 115.5, 61.3, 45.3, 30.0, 29.3, 20.2, 18.2 14.3, 13.5. IR (KBr) (vmax, cm−1) 3389, 2964, 1737, 1658, 1593, 1526, 1424, 1372, 1297, 1233, 1129, 1069, 1030, 862, 802, 752, 551. HRMS (ESI-TOF) m/z Calcd for C15H21NNaO4+ [M + Na]+ 302.1363, found 302.1368. Ethyl 5-acetyl-1-cyclopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 7i. Yield 60%, 157.97 mg; pale yellow solid; mp 86.9−88.1 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.51 (s, 1H, CH), 4.39 (q, J = 7.2 Hz, 2H, OCH2), 2.92 (s, 1H, NCH), 2.87 (s, 3H, CH3), 2.52 (s, 3H, CH3), 1.40−1.37 (m, 5H, CH2 CH3), 0.84−0.83 (m, 2H, CH2). 13C NMR (CDCl3, 100 MHz) δ 196.2, 164.8, 161.1, 160.3, 144.0, 116.3, 116.1, 61.4, 29.7, 29.3, 20.1, 14.3, 12546

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry Ethyl 5-acetyl-1-(furan-2-ylmethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 8f. Yield 78%, 236.58 mg; white solid; mp 114.2−114.8 °C. 1H NMR (CDCl3, 400 MHz, TMS) δ 8.47 (s, 1H, CH), 7.26−7.21 (m, 1H, CH), 6.40−6.25 (m, 2H, CH), 5.31 (s, 2H, NCH2), 4.33 (q, J = 7.2 Hz, 2H, OCH2), 2.88 (s, 3H, CH3), 2.47 (s, 3H, CH3), 1.32 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) δ 195.6, 163.6, 157.7, 158.9, 156.9, 147.3, 143.2, 141.3, 115.7, 115.0, 109.7, 109.4, 60.4, 40.2, 28.4, 17.5, 13.3. IR (KBr) (vmax, cm−1) 3413, 1713, 1662, 1589, 1521, 1439, 1380, 1247, 1028, 860, 802, 778, 569. HRMS (ESI-TOF) m/z Calcd for C16H18NO5+ [M + H]+ 304.1174, found 304.1179.

■

(7) Jessen, H. J.; Gademann, K. 4-Hydroxy-2-pyridone alkaloids: Structures and synthetic approaches. Nat. Prod. Rep. 2010, 27 (8), 1168−1185. (8) Qun, L.; A, M. L.; L, S. L. The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors. Med. Res. Rev. 2000, 20 (4), 231− 293. (9) For examples of pharmaceutically active compounds containing the pyridone scaffold, see: (a) Dragovich, P. S.; Prins, T. J.; Zhou, R.; Brown, E. L.; Maldonado, F. C.; Fuhrman, S. A.; Zalman, L. S.; Tuntland, T.; Lee, C. A.; Patick, A. K.; Matthews, D. A.; Hendrickson, T. F.; Kosa, M. B.; Liu, B.; Batugo, M. R.; Gleeson, J.-P. R.; Sakata, S. K.; Chen, L.; Guzman, M. C.; Meador, J. W.; Ferre, R. A.; Worland, S. T. Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 6. Structure− Activity Studies of Orally Bioavailable, 2-Pyridone-Containing Peptidomimetics. J. Med. Chem. 2002, 45 (8), 1607−1623. (b) Lo Presti, E.; Boggia, R.; Feltrin, A.; Menozzi, G.; Dorigo, P.; Mosti, L. 3Acetyl-5-acylpyridin-2(1H)-ones and 3-acetyl-7,8-dihydro-2,5(1H,6H)-quinolinediones: synthesis, cardiotonic activity and computational studies. Farmaco 1999, 54 (7), 465−474. (c) Amr, A.-G. E.; Abdulla, M. M. Anti-inflammatory profile of some synthesized heterocyclic pyridone and pyridine derivatives fused with steroidal structure. Bioorg. Med. Chem. 2006, 14 (13), 4341−4352. (d) Cocco, M. T.; Congiu, C.; Onnis, V. Synthesis and antitumour activity of 4hydroxy-2-pyridone derivatives. Eur. J. Med. Chem. 2000, 35 (5), 545−552. (e) Kaminski, J. J.; Doweyko, A. M. Antiulcer Agents. 6. Analysis of the in Vitro Biochemical and in Vivo Gastric Antisecretory Activity of Substituted Imidazo[1,2-a]pyridines and Related Analogues Using Comparative Molecular Field Analysis and Hypothetical Active Site Lattice Methodologies. J. Med. Chem. 1997, 40 (4), 427− 436. (10) 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 (3), 660−663. (11) Tu, X.-J.; Fan, W.; Hao, W.-J.; Jiang, B.; Tu, S.-J. ThreeComponent Bicyclization Providing an Expedient Access to Pyrano[2′,3′:5,6]pyrano[2,3-b]pyridines and Its Derivatives. ACS Comb. Sci. 2014, 16 (11), 647−651. (12) (a) Li, Y.; Cao, X.; Liu, Y.; Wan, J.-P. Regioselective threecomponent synthesis of 2,3-disubstituted quinolines via the enaminone modified Povarov reaction. Org. Biomol. Chem. 2017, 15 (45), 9585−9589. (b) Stout, D. M.; Meyers, A. I. Recent advances in the chemistry of dihydropyridines. Chem. Rev. 1982, 82 (2), 223−243. (13) (a) Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Metal-Free Multicomponent Syntheses of Pyridines. Chem. Rev. 2014, 114 (21), 10829−10868. (b) Lu, L. L.; Xu, H.; Zhou, P.; Yu, F. C. Progress in Synthesis of 1,4-Dihydropyridines. Youji Huaxue 2016, 36, 2858−2879. (14) Baron, H.; Remfry, F. G. P.; Thorpe, J. F. CLXXV.-The formation and reactions of imino-compounds. Part I. Condensation of ethyl cyanoacetate with its sodium derivative. J. Chem. Soc., Trans. 1904, 85, 1726−1761. (15) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. Direct Alkenylation and Alkylation of Pyridone Derivatives by Ni/AlMe3 Catalysis. J. Am. Chem. Soc. 2009, 131 (44), 15996−15997. (16) Hyster, T. K.; Rovis, T. An improved catalyst architecture for rhodium(iii) catalyzed C-H activation and its application to pyridone synthesis. Chem. Sci. 2011, 2 (8), 1606−1610. (17) Sainte, F.; Serckx-Poncin, B.; Hesbain-Frisque, A. M.; Ghosez, L. A Diels-Alder route to pyridone and piperidone derivatives. J. Am. Chem. Soc. 1982, 104 (5), 1428−1430. (18) Yan, S.; Chen, Y.; Liu, L.; He, N.; Lin, J. Three-component solvent-free synthesis of highly substituted bicyclic pyridines containing a ring-junction nitrogen. Green Chem. 2010, 12 (11), 2043−2052. (19) Hyster, T. K.; Rovis, T. Pyridine synthesis from oximes and alkynesviarhodium(iii) catalysis: Cp* and Cpt provide complementary selectivity. Chem. Commun. 2011, 47 (43), 11846−11848.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01788. Copies of 1H NMR and 13C NMR spectra (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

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

Lijuan Yang: 0000-0003-1303-6398 Chao Huang: 0000-0003-1214-6608 Author Contributions §

H.B. and R.S. contributed equally.

Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Nos. 21662046 and 21202142). REFERENCES

(1) U.S. Environmental Protection Agency, http://www.epa.gov (accessed March 1, 2014). (2) Dunn, P. J. The importance of green chemistry in process research and development. Chem. Soc. Rev. 2012, 41, 1452−1461. (3) (a) Sheldon, R. A. Metrics of Green Chemistry and Sustainability: Past, Present, and Future. ACS Sustainable Chem. Eng. 2018, 6 (1), 32−48. (b) Erythropel, H. C.; Zimmerman, J. B.; de Winter, T. M.; Petitjean, L.; Melnikov, F.; Lam, C. H.; Lounsbury, A. W.; Mellor, K. E.; Jankovic, N. Z.; Tu, Q.; Pincus, L. N.; Falinski, M. M.; Shi, W.; Coish, P.; Plata, D. L.; Anastas, P. T. The Green ChemisTREE: 20 years after taking root with the 12 principles. Green Chem. 2018, 20, 1929−1961. (4) (a) Caddick, S. Microwave assisted organic reactions. Tetrahedron 1995, 51 (38), 10403−10432. (b) Polshettiwar, V.; Varma, R. S. Aqueous microwave chemistry: a clean and green synthetic tool for rapid drug discovery. Chem. Soc. Rev. 2008, 37 (8), 1546−1557. (c) Appukkuttan, P.; Mehta, V. P.; Van der Eycken, E. V. Microwave-assisted cycloaddition reactions. Chem. Soc. Rev. 2010, 39 (5), 1467−1477. (d) Langa, F.; de la Cruz, P.; de la Hoz, A.; DiazOrtiz, A.; Diez-Barra, E. Microwave irradiation: more than just a method for accelerating reactions. Contemp. Org. Synth. 1997, 4 (5), 373−386. (5) (a) Polshettiwar, V.; Varma, R. S. Microwave-Assisted Organic Synthesis and Transformations using Benign Reaction Media. Acc. Chem. Res. 2008, 41 (5), 629−639. (b) Nikolai, K. MicrowaveAssisted Reactions in Organic SynthesisAre There Any Nonthermal Microwave Effects? Angew. Chem., Int. Ed. 2002, 41 (11), 1863−1866. (6) Tuson, R. V. XXII.-Note on an alkaloid contained in the seeds of the Ricinus communis, or castor-oil plant. J. Chem. Soc. 1864, 17, 195−197. 12547

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548

Article

The Journal of Organic Chemistry (20) For domino integration strategy, see: (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; John Wiley & Sons: Weinheim, 2006. (b) Zeng, X.; Ni, Q.; Raabe, G.; Enders, D. A Branched Domino Reaction: Asymmetric Organocatalytic TwoComponent Four-Step Synthesis of Polyfunctionalized Cyclohexene Derivatives. Angew. Chem., Int. Ed. 2013, 52 (10), 2977−2980. (21) For multicomponent reactions, see: (a) Dömling, A.; Wang, W.; Wang, K. Chemistry and Biology of Multicomponent Reactions. Chem. Rev. 2012, 112 (6), 3083−3135. (22) Wan, J.-P.; Gan, L.; Liu, Y. Transition metal-catalyzed C−H bond functionalization in multicomponent reactions: a tool toward molecular diversity. Org. Biomol. Chem. 2017, 15 (43), 9031−9043. (23) For atom-economical, see: Trost, B. The atom economy–a search for synthetic efficiency. Science 1991, 254 (5037), 1471−1477. (24) (a) Nicolas, I.; Rodolfo, L. Heterocycles as Key Substrates in Multicomponent Reactions: The Fast Lane towards Molecular Complexity. Chem. - Eur. J. 2008, 14 (28), 8444−8454. (b) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Multicomponent reactions: advanced tools for sustainable organic synthesis. Green Chem. 2014, 16 (6), 2958−2975. (25) For step-economical, see: Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Function-Oriented Synthesis, Step Economy, and Drug Design. Acc. Chem. Res. 2008, 41 (1), 40−49. (26) Chen, X. B.; Bai, H. R.; Huang, C. Concise Synthesis of Quinolinone Derivatives. Youji Huaxue 2017, 37 (4), 881−888. (27) Bai, H. R.; Sun, R. R.; Chen, X. B.; Yang, L. J.; Huang, C. Microwave-Assisted, Solvent-Free, Three-Component Domino Protocol: Efficient Synthesis of Polysubstituted-2-Pyridone Derivatives. ChemistrySelect 2018, 3 (17), 4635−4638. (28) Bai, H. R.; Liu, F. J.; Wang, X. J.; Wang, P.; Huang, C. ThreeComponent One-Pot Approach to Highly Efficient and Sustainable Synthesis of the Functionalized Quinolones via Linear/Branched Domino Protocol, Key Synthetic Methods for the Floxacin of Quinolone Drugs. ACS Omega 2018, 3, 11233−11251. (29) (a) Wu, A.; Isaacs, L. Self-Sorting: The Exception or the Rule ? J. Am. Chem. Soc. 2003, 125 (16), 4831−4835. (b) Yaragorla, S.; Dada, R. Amine-Triggered Highly Facile Oxidative Benzannulation Reaction for the Synthesis of Anthranilates under Solvent-Free Calcium(II) Catalysis. ACS Omega 2017, 2 (8), 4859−4869.

12548

DOI: 10.1021/acs.joc.8b01788 J. Org. Chem. 2018, 83, 12535−12548