Next Article in Journal
Electrochemical Characterization of the Antioxidant Properties of Medicinal Plants and Products: A Review
Previous Article in Journal
Neuroprotective Effects of Carnosic Acid: Insight into Its Mechanisms of Action
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 5
10.3390/molecules28052304
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Hydrogen Bond Assisted Three-Component Tandem Reactions to Access N-Alkyl-4-Quinolones

by
Huanhuan Liu
1,2,†,
Huadan Liu
1,2,†,
Enhua Wang
3,
Liangqun Li
1,2,
Zhongsheng Luo
1,2,
Jiafu Cao
1,2,
Jialin Chen
1,2,
Lishou Yang
1,2,* and
Xiaosheng Yang
1,2,*
1
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China
2
The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China
3
Department of Food and Medicine, Guizhou Vocational College of Agriculture, Qingzhen 551400, China
*
Authors to whom correspondence should be addressed.
†
The authors contributed equally to this work.
Molecules 2023, 28(5), 2304; https://doi.org/10.3390/molecules28052304
Submission received: 7 February 2023 / Revised: 15 February 2023 / Accepted: 21 February 2023 / Published: 2 March 2023
Browse Figures
Review Reports Versions Notes

Abstract

:
Hydrogen-bonding catalytic reactions have gained great interest. Herein, a hydrogen-bond-assisted three-component tandem reaction for the efficient synthesis of N-alkyl-4-quinolones is described. This novel strategy features the first proof of polyphosphate ester (PPE) as a dual hydrogen-bonding catalyst and the use of readily available starting materials for the preparation of N-alkyl-4-quinolones. The method provides a diversity of N-alkyl-4-quinolones in moderate to good yields. The compound 4h demonstrated good neuroprotective activity against N-methyl-ᴅ-aspartate (NMDA)-induced excitotoxicity in PC12 cells.

Graphical Abstract

1. Introduction

A valuable class of nitrogen-containing heterocycles is 4-Quinolone, which widely exists in natural products [1,2], synthetic blocks [3,4,5,6], and bioactive molecules [7,8,9,10,11,12,13]. Typical N-alkyl-4-quinolone derivatives are drugs such as ciprofloxacin, norfloxacin, and oxolinic acid, which have emerged as potent antibiotics (Figure 1). Traditional synthetic approaches to the 4-quinolone framework are based on cyclocondensation involving Conrad–Limpach [14,15,16,17], Niementowski [18,19,20,21] and Camps-type reactions [22,23,24], which usually suffer from harsh reaction conditions, limitation of substrate scope, and the requirement of commercially unavailable starting materials. Recently, several elegant procedures have focused on the use of transition-metal catalysis [23,24,25,26,27,28,29,30,31] and tandem reactions from o-alkynylbenzamides/aldehydes or o-haloaryl acetylenic ketones/amines (Scheme 1a) [32,33,34,35,36]. However, these successful routes require transition-metal catalysis, multistep procedures, long reaction time, and special precursors such as prehaloaryl acetylenic ketones. Additionally, most of these methods failed to give N-alkyl-substituted 4-quinolones, that are featured in many clinically used drugs. Therefore, the implementation of mechanistically different transformations to achieve structural diversity in 4-quinolone synthesis from easily accessible raw materials still remains a large need.
Hydrogen-bonding interactions play a crucial role in catalysis, especially in the field of asymmetric catalysis [37]. Organic chemists have found that small molecules possessing distinct hydrogen bond donors, such as O-H, N-H, and S-H functional groups, catalyze a range of C-C and C-heteroatom bond-forming reactions, although the hydrogen-bonding interactions are weak [38,39,40,41,42,43]. To date, hydrogen-bonding catalysts possess a wide range of functional and structural frameworks are explored, including thioureas [44,45], prolines [46,47], sulfonamides [48] and chiral phosphoric acid (CPA) [49,50,51,52,53,54,55,56,57].
Investigations of CPA in the field of hydrogen-bonding catalytic chemical reactions made clear that the P=O and O-H serve as hydrogen bond acceptor and donor, respectively [49,50,51,52,53,54,55,56,57]. Previous reports show that polyphosphate ester (PPE) could activate the nitrogen functional group toward nucleophilic attack, and serve as alkylating reagents [58]. Recently, our group reported polyphosphoric acid (PPA) promoted tandem reactions for the synthesis of heterocycles, which revealed that PPA is an effective condensation reagent [59,60]. On the basis of the previous work, we envisioned that N-alkyl-4-quinolones could be synthesized via the three-component tandem reactions of readily accessible 2-aminoacetophenones, aldehydes and alcohols using PPA (Scheme 1b). Specifically, PPE 6 and condensation product 7 were formed in the presence of PPA, and subsequent formation of PPE-7 complex 8 via hydrogen-bonding interactions, which are the driving force for the formation of 9. Immediately, 9 undergoes alkylation to produce intermediate 10 followed by a tautomerization to deliver the 4-quinolone 4y.

2. Results and Discussion

To support this hypothesis, several control experiments and density functional theory (DFT) calculations were performed (Scheme 2). Fortunately, the desired product 4y could be obtained directly from 1a, 2a and 3c in 37% yield (Scheme 2a). As depicted in Scheme 2b(1), condensation product 7 was afforded in the 32% isolated yield. Subsequently, 7 was also employed as substrate and the 4-quinolone 4y was obtained in 35% yield (Scheme 2b(2)). Furthermore, PPE 6 was detected by 31P NMR (Scheme 2b(3), see Supplementary Materials for details). As shown in Scheme 2c, diphosphoric acid ethyl ester 11 (a model PPE) reacts with 7 to produce complex 12 with a computed free energy of 1.6 kcal/mol. Subsequently, the intermediate 13 was generated via transition state TS1, which then undergoes N-alkylation to yield product 4y. The DFT calculations suggest that this process is thermodynamically feasible. Additionally, the generation of such a PPE-7 complex 8 was further verified by 31P NMR (see Supplementary Materials for details).
Next, we commenced our studies using 2-aminoacetophenone 1a, benzaldehyde 2a and 1-octanol 3a as model substrates to optimize the reaction conditions. A mixture of 1a, 2a, 3a and PPA (5.0 equiv.) in DMF refluxed for 1 h under nitrogen atmosphere to give the target compound 4a in 38% yield (Table S1, entry 1). PPA amount, time and temperature screening revealed that 1.0 equiv., 3 h and reflux was the best choice (see Table S1 for more details). We further screened the additives including P2O5 and PPA/P2O5 (Table 1, entries 1–2). According to the screening results, PPA was identified as the best. The effect of solvent was also surveyed, yet the results were inferior to those of DMF (Table 1, entries 3–8 vs. Table S1, entry 7). Subsequently, reaction was performed in the presence of 4 Å MS indicated that 4 Å MS had no effect on this transformation (Table 1, entry 9). Finally, the optimized reaction conditions were determined as follows: 1a (1 equiv.), 2a (1.2 equiv.), 3a (1 mL) and PPA (1.0 equiv.) in DMF refluxed for 3 h under a nitrogen atmosphere (Table S1, entry 7). Under the optimized conditions, a gram scale reaction was conducted and provided 4a in 70% yield (Table 1, entry 10).
With the optimized reaction conditions in hand, we then explored the scope and limitations of this reaction (Table 2). Gratifyingly, diverse 2-aminoacetophenones, aldehydes and alcohols were compatible with the reaction, producing the target 4-quinolones 4a-4ao in satisfactory yields. As can be seen, the electron-donating group (methyl or ethyl) on benzaldehyde led to higher yields, while the electron-withdrawing group (F, Cl or Br) gave lower yields (4a, 4e and 4f vs. 4b–4d). It is noteworthy that naphthaldehyde, thenaldehyde and cyclohexanecarboxaldehyde also underwent smooth transformation to give corresponding 4-quinolones (4g–4i). Then, the scope of the reaction was evaluated regarding various aminoacetophenones with different substituents, and it was found that electron-withdrawing groups, such as F, Cl and Br, provided lower yield (4j–4l and 4n–4p vs. 4m and 4q). We further examined the scope of alcohol substrates. Different alcohols worked well with aminoacetophenones and aldehydes yielding diverse N-alkyl-substituted 4-quinolones 4r–4ao in moderate to good yields (48–84%). It was also observed that this reaction was sensitive to the steric hindrance of the alcohols. The yield was decreased with increasing the steric hindrance (e.g., 4r vs. 4y vs. 4af vs. 4am vs. 4an vs. 4ao). Next, we carried out a reaction between 2-aminoacetophenone, benzaldehyde and phenol. Unfortunately, phenol was not tolerated in this case, and the target product 4ap was not detected.
Interestingly, phenols were compatible with the reaction in the presence of Pd/C (Table 3, optimization study see Table S2 for more details). A π-alkene–palladium complex might be formed [61], which would promote the cyclization of intermediate 8. However, the use of palladium catalysts proved to be less effective in the case of alcohols (Table S1, entries 12–14 and Table S2, entry 18).
In order to gain deeper insight into this reaction, phosphates (14 and 15) were subjected to the reaction, giving the target products in 29% and 36% yields, respectively (Scheme 3a). The electron-withdrawing F substituent has long been proposed to act as a nonclassical hydrogen bond acceptor on the aryl ring [62,63]. We then introduced a hydrogen-bonding acceptor to 2-aminochalcone; 16, featuring the electron-withdrawing F, was tested. The 16 presented product 4u with a better yield then that of 4r (Scheme 3b vs. Scheme 3c). N-methyl substituted chalcone 17 provided the desired product 4r in 2% yield, probably owing to the fact that hydrogen-bonding interactions were weakened by the methyl (Scheme 3d). These observations collectively suggested that the hydrogen bonds between PPE and 2-aminochalcones might be formed.
Previous studies show that quinolones were identified as potent NMDA/glycine antagonists with neuroprotective properties [58,64,65]. Thus, all the 4-quinolones were evaluated for their neuroprotective activity against NMDA-induced injury in PC12 cells. The substituent on the nitrogen of 4-quinolone had effect on the activity. N-octyl -substituted compounds exhibited better activity than other targeted compounds (Figure S2). Among the compounds, the most active is compound 4h, exhibiting neuroprotective potency similar to the MK-801 at 20 μM (Figure 2). To investigate the possible binding mode for this series, 4h was docked into the NMDA receptor. In the binding mode, 4h fitted well in the active pocket. The binding energies of 4h and DCKA were −7.46 kcal/mol and −7.65 kcal/mol, respectively (see Figure S3 for more details).

3. Materials and Methods

3.1. General Information

Fetal bovine serum, Dulbecco’s modified Eagle’s medium, penicillin and streptomycin were obtained from Gibco (Gibco, Paisley, UK). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and NMDA were purchased from Sigma-Aldrich (Saint Louis, MO, USA). MK-801 was from MCE (Shanghai, China). PC12 cells from Institute of Cell Biology (Chinese Academy of Sciences, Shanghai, China). Unless otherwise noted, all reagents, catalysts and solvents were purchased from commercial suppliers and used without further purification unless otherwise noted. Column Chromatography was performed with silica gel (200–300 mesh). Melting points were determined using an X-4 melting point apparatus with microscope. The IR spectra were recorded with a Mattson FTIR spectrometer 5000. Absorption maxima were measured in cm−1. 1H NMR (600 MHz) and 13C NMR (151 MHz) spectra were achieved in CDCl3 on a Bruker AVANCE 600 MHz spectrometer. High-resolution mass spectra were measured on a ThermoFish QE Focus facility (Waltham, MA, USA).

3.2. Synthesis of Compounds 4a–4ao

General procedure. To a solution of DMF (0.5 mL) was added 2-aminoacetophenones 1 (0.37 mmol), benzaldehydes 2 (0.44 mmol), alcohols 3 (1 mL) and PPA (0.37 mmol) in a 50 mL round bottom flask. The reaction mixture was refluxed for 3 h. The solution was quenched with water and the organic layer was dried over Na2SO4, filtered and evaporated. The resulting crude compound was purified by silica gel column chromatography using hexane/ethyl acetate mixtures to afford the corresponding products 4a–4ao.
1-Octyl-2-phenylquinolin-4(1H)-one (4a) [32]. Yellow solid; Yield: 81%; Mp: 58.8–61.5 °C; IR (KBr plate) νmax 2945, 2920, 1617, 1594, 1358, 835, 694. 1H NMR (600 MHz, CDCl3) δ 8.26–8.24(dd, J = 8.3, 1.5 Hz, 1H, CH Ar), 8.13–8.13 (m, 3H, CH Ar), 7.75–7.72 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.56–7.54 (dd, J = 8.3, 6.9 Hz, 2H, CH Ar), 7.52–7.47 (m, 2H, CH Ar), 7.19 (s, 1H, CH), 4.30–4.28 (t, J = 6.4 Hz, 2H, CH2), 2.03–1.98 (dt, J = 15.0, 6.6 Hz, 2H, CH2), 1.64–1.59 (m, 2H, CH2),1.48–1.43 (m, 2H, CH2), 1.42–1.38 (m, 2H, CH2), 1.37–1.33 (tq, J = 7.2, 3.9, 3.0 Hz, 4H, CH2), 0.95–0.93 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.29 (CO), 158.89, 149.25, 140.52, 129.91, 129.20, 128.75, 127.61, 125.26, 121.77, 120.56, 98.60, 68.47, 31.85, 29.36, 29.27, 28.99, 26.17, 22.70, 14.14. HRMS Exact mass calcd. for C23H28ON [M + H]+: 334.21654; found: 334.21594.
2-(4-Fluorophenyl)-1-octylquinolin-4(1H)-one (4b). Yellow solid; Yield: 77%; Mp: 47.6–57.1 °C; IR (KBr plate) νmax 2920, 2850, 1610, 1590, 1353, 824, 626. 1H NMR (600 MHz, CDCl3) δ 8.25–8.23 (dd, J = 8.3, 1.5 Hz, 1H, CH Ar), 8.14–8.09 (m, 3H, CH Ar), 7.74–7.71 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.52–7.49 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H, 1 CH Ar), 7.24–7.20 (m, 2H, CH Ar), 7.13 (s, 1H, CH), 4.30–4.28 (t, J = 6.4 Hz, 2H, CH2), 2.03–1.98 (m, 2H, CH2), 1.62–1.58 (p, J = 7.4 Hz, 2H, CH2), 1.48–1.43 (dq, J = 9.2, 6.6 Hz, 2H, CH2), 1.41–1.37 (m, 2H, CH2), 1.35–1.33 (qd, J = 6.7, 2.7 Hz, 4H, CH2), 0.94–0.92 (t, J = 6.9 Hz, 3H, CH3).13C NMR (151 MHz, CDCl3) δ 163.72 (q, 1JCF = 249.15), 162.40 (CO), 157.72, 149.17, 136.60, 136.58, 130.03, 129.41 (q, 3JCF = 9.06), 129.08, 125.33, 121.78, 120.46, 115.64 (q, 2JCF = 25.67), 98.22, 68.51, 31.83, 29.35, 29.25, 28.98, 26.16, 22.68, 14.13. HRMS Exact mass calcd. for C23H27ONF [M + H]+: 352.20712; found: 352.20651.
2-(4-Chlorophenyl)-1-octylquinolin-4(1H)-one (4c). Yellow solid; Yield: 78%; Mp: 62.1–65.1 °C; IR (KBr plate) νmax 2924, 2848, 1617, 1593, 1352, 818, 668. 1H NMR (600 MHz, CDCl3) δ 8.25–8.23 (dd, J = 8.2, 1.5 Hz, 1H, CH Ar), 8.11–8.07 (m, 3H, CH Ar), 7.74–7.72 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H, CH Ar), 7.53–7.49 (m, 3H, CH Ar), 7.13 (s, 1H, CH), 4.30–4.28 (t, J = 6.4 Hz, 2H, CH2), 2.03–1.98 (m, 2H, CH2), 1.63–1.58 (p, J = 7.4 Hz, 2H, CH2), 1.48–1.44 (dq, J = 9.2, 6.7 Hz, 2H, CH2), 1.41–1.37 (m, 2H, CH2), 1.36–1.32 (qd, J = 6.6, 2.7 Hz, 4H, CH2), 0.94–0.92 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.46 (CO), 157.49, 149.16, 138.83, 135.38, 130.08, 129.12, 128.90, 128.86, 125.47, 121.80, 120.57, 98.17, 68.54, 31.83, 29.35, 29.25, 28.97, 26.16, 22.68, 14.13. HRMS Exact mass calcd. for C23H27ONCl [M + H]+: 368.17757; found: 368.17725.
2-(4-Bromophenyl)-1-octylquinolin-4(1H)-one (4d). Yellow solid; Yield: 70%; Mp: 84.2–86.4 °C; IR (KBr plate) νmax 2921, 2852, 1652, 1592, 1361, 824, 668. 1H NMR (600 MHz, CDCl3) δ 8.25–8.23(dd, J = 8.2, 1.5 Hz, 1H, CH Ar), 8.11–8.10 (d, J = 8.4 Hz, 1H, CH Ar), 8.03–8.01 (m, 2H, CH Ar), 7.75–7.72 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.67–7.65 (m, 2H, CH Ar), 7.53–7.50 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H, CH Ar), 7.13 (s, 1H, CH), 4.30–4.28 (t, J = 6.4 Hz, 2H, CH2), 2.03–1.98 (m, 2H, CH2), 1.63–1.58 (p, J = 7.4 Hz, 2H, CH2), 1.48–1.43 (p, J = 6.6 Hz, 2H, CH2), 1.41–1.37 (m, 2H, CH2), 1.36–1.32 (qd, J = 6.6, 2.7 Hz, 4H, CH2), 0.94–0.92 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.50 (CO), 157.52, 149.14, 139.25, 131.86, 130.11, 129.15, 129.11, 125.50, 123.75, 121.81, 120.59, 98.12, 68.56, 31.83, 29.34, 29.25, 28.97, 26.16, 22.68, 14.13. HRMS Exact mass calcd. for C23H27ONBr [M + H]+: 412.12705; found: 412.12671.
1-Octyl-2-p-tolyl-quinolin-4(1H)-one (4e). Yellow solid; Yield: 83%; Mp: 72.0–74.0 °C; IR (KBr plate) νmax 2924, 2853, 1621, 1593, 1356, 816, 612. 1H NMR (600 MHz, CDCl3) δ 8.24–8.22 (dd, J = 8.3, 1.5 Hz, 1H, CH Ar), 8.12–8.11 (d, J = 8.4 Hz, 1H, CH Ar), 8.04–8.02 (d, J = 8.1 Hz, 2H, CH Ar), 7.73–7.70 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.51–7.48 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H, CH Ar), 7.35–7.33 (m, 2H, CH Ar), 7.17 (s, 1H, CH), 4.30–4.28 (t, J = 6.4 Hz, 2H, CH2), 2.46 (s, 3H, CH3), 2.02–1.98 (m, 2H, CH2), 1.63–1.58 (p, J = 7.4 Hz, 2H, CH2), 1.48–1.43 (m, 2H, CH2), 1.41–1.37 (m, 2H, CH2), 1.36–1.33 (tt, J = 6.9, 3.1 Hz, 4H, CH2), 0.94–0.92 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.24 (CO), 158.84, 149.19, 139.28, 137.61, 129.86, 129.47, 129.04, 127.47, 125.10, 121.74, 120.50, 98.42, 68.43, 31.83, 29.35, 29.26, 28.99, 26.17, 22.68, 21.35, 14.13. HRMS Exact mass calcd. for C24H29ON [M + H]+: 348.23219; found: 348.23172.
2-(4-Ethylphenyl)-1-octylquinolin-4(1H)-one (4f). White solid; Yield: 81%; Mp: 59.4–62.6 °C; IR (KBr plate) νmax 2924, 2850, 1613, 1593, 1360, 824, 616. 1H NMR (600 MHz, CDCl3) δ 8.24–8.23 (dd, J = 8.3, 1.3 Hz, 1H, CH Ar), 8.12–8.11(d, J = 8.4 Hz, 1H, CH Ar), 8.06–8.04 (m, 2H, CH Ar), 7.73–7.70 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.51–7.48 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H, CH Ar), 7.38–7.37 (d, J = 8.2 Hz, 2H, CH Ar), 7.17 (s, 1H, CH), 4.30–4.28 (t, J = 6.4 Hz, 2H, CH2), 2.78–2.74 (q, J = 7.6 Hz, 2H, CH2), 2.02–1.98 (m, 2H, CH2), 1.63–1.58 (p, J = 7.4 Hz, 2H, CH2), 1.48–1.42 (m, 2H, CH2), 1.41–1.37 (m, 2H, CH2), 1.37–1.33(td, J = 8.0, 7.0, 3.1 Hz, 4H, CH2), 1.33–1.30 (t, J = 7.6 Hz, 3H, CH3), 0.94–0.92 (t, J = 6.9 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.20 (CO), 158.93, 149.24, 145.62, 137.95, 129.84, 129.09, 128.29, 127.58, 125.09, 121.74, 120.49, 98.49, 68.42, 31.84, 29.36, 29.26, 28.99, 28.74, 26.17, 22.69, 15.62, 14.13. HRMS Exact mass calcd. for C25H32ON [M + H]+: 362.24784; found: 362.24728.
2-Naphthalen-1-yl-1-octylquinolin-4(1H)-one (4g). Colorless oil; Yield: 62%; IR (KBr plate) νmax 2940, 2851, 1619, 1591, 1361, 836, 648. 1H NMR (600 MHz, CDCl3) δ 8.33–8.32(dd, J = 8.3, 1.5 Hz, 1H, CH Ar), 8.17–8.13 (dd, J = 19.8, 8.4 Hz, 2H, CH Ar), 7.97–7.95 (t, J = 8.1 Hz, 2H, CH Ar), 7.79–7.76 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.73–7.71 (dd, J = 7.0, 1.3 Hz, 1H, CH Ar), 7.62–7.57 (m, 2H, CH Ar), 7.55–7.52 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H, CH Ar), 7.50–7.47 (ddd, J = 8.3, 6.7, 1.4 Hz, 1H, CH Ar), 7.04 (s, 1H, CH), 4.25–4.22 (t, J = 6.5 Hz, 2H, CH2), 2.00–1.96 (m, 2H, CH2), 1.61–1.56 (dt, J = 15.4, 7.4 Hz, 2H, CH2), 1.45–1.40 (m, 2H, CH2), 1.39–1.31 (m, 6H, CH2), 0.92 (t, J = 6.9 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 161.75 (CO), 160.61, 149.02, 139.50, 133.96, 131.31, 130.02, 129.17, 128.93, 128.35, 127.24, 126.49, 125.93, 125.85, 125.55, 125.35, 121.84, 120.39, 102.84, 68.64, 31.82, 29.34, 29.24, 28.95, 26.13, 22.68, 14.13. HRMS Exact mass calcd. for C27H30ON [M + H]+: 384.23329; found: 384.23187.
2-Thiophen-2-yl-1-octylquinolin-4(1H)-one (4h). White solid; Yield: 69%; Mp: 40.2–43.4 °C; IR (KBr plate) νmax 2925, 2854, 1616, 1591, 1361, 826, 668. 1H NMR (600 MHz, CDCl3) δ 8.19–8.17 (dd, J = 8.3, 1.5 Hz, 1H, CH Ar), 8.05–8.04 (d, J = 8.4 Hz, 1H, CH Ar), 7.72–7.68 (m, 2H, CH Ar), 7.48–7.45 (m, 2H, CH Ar), 7.17–7.16 (dd, J = 5.0, 3.7 Hz, 1H, CH Ar), 7.11 (s, 1H, CH), 4.26–4.24 (t, J = 6.4 Hz, 2H, CH2), 2.01–1.96 (m, 2H, CH2), 1.62–1.57 (p, J = 7.9, 7.4 Hz, 2H, CH2), 1.47–1.45 (m, 2H, CH2), 1.41–1.38 (m, 2H, CH2), 1.37–1.33 (td, J = 10.9, 10.0, 4.5 Hz, 4H, CH2), 0.95–0.93 (t, J = 6.7 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.09 (CO), 153.40, 149.08, 145.93, 130.01, 128.77, 128.27, 127.88, 125.43, 125.11, 121.79, 120.75, 96.97, 68.50, 31.85, 29.38, 29.27, 28.97, 26.16, 22.71, 14.16. HRMS Exact mass calcd. for C21H26ONS [M + H]+: 340.17296; found: 340.17264.
2-Cyclohexyl-1-octylquinolin-4(1H)-one (4i). Colorless oil; Yield: 41%; IR (KBr plate) νmax 2910, 2821, 1639, 1599, 1368, 831, 628. 1H NMR (600 MHz, CDCl3) δ 8.18–8.17 (d, J = 8.1 Hz, 1H, CH Ar), 8.00–7.99 (d, J = 8.4 Hz, 1H, CH Ar), 7.68–7.65 (t, J = 7.6 Hz, 1H, CH Ar), 7.46–7.43 (t, J = 7.7 Hz, 1H, CH Ar), 6.65 (s, 1H, CH), 4.22–4.20 (t, J = 6.4 Hz, 2H, CH2), 2.91–2.86 (tt, J = 12.1, 3.4 Hz, 1H, CH), 2.06–2.04 (d, J = 11.2 Hz, 2H, CH2), 1.98–1.90 (m, 5H, CH2), 1.82–1.80 (d, J = 12.8 Hz, 1H, CH2), 1.67–1.56 (m, 4H, CH2), 1.53–1.41 (m, 4H, CH2), 1.40–1.33 (m, 6H, CH2), 0.92 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 168.19 (CO), 161.98, 148.66, 129.56, 128.31, 124.63, 121.69, 120.43, 98.50, 68.24, 48.20, 32.96, 31.83, 29.35, 29.24, 28.98, 26.57, 26.16, 26.13, 22.68, 14.12. HRMS Exact mass calcd. for C23H34ON [M + H]+: 340.26349; found: 340.26306.
2-(4-Chlorophenyl)-7-fluoro-1-octylquinolin-4(1H)-one (4j). Yellow solid; Yield: 65%; Mp: 73.3–75.8 °C; IR (KBr plate) νmax 2919, 2851, 1628, 1594, 1354, 815, 667. 1H NMR (600 MHz, CDCl3) δ 8.24–8.21 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.08–8.06 (m, 2H, CH Ar), 7.73–7.70 (dd, J = 10.4, 2.5 Hz, 1H, CH Ar), 7.52–7.49 (m, 2H, CH Ar), 7.28–7.26 (m, 1H, CH Ar), 7.10 (s, 1H, CH), 4.30–4.28 (t, J = 6.4 Hz, 2H, CH2), 2.02–1.97 (m, 2H, CH2), 1.62–1.57 (p, J = 7.4 Hz, 2H, CH2), 1.47–1.42 (m, 2H, CH2), 1.41–1.37 (m, 2H, CH2), 1.36–1.32 (qd, J = 6.7, 2.8 Hz, 4H, CH2), 0.94–0.91 (t, J = 6.9 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.79 (q, 1JCF = 249.15), 162.55 (CO), 158.75, 150.46 (q, 3JCF = 12.08), 138.43, 135.68, 128.95, 128.86, 124.17 (q, 3JCF = 10.57), 117.49, 115.51 (q, 2JCF = 25.67), 112.79 (q, 2JCF = 19.63), 97.73, 68.67, 31.82, 29.33, 29.24, 28.93, 26.13, 22.67, 14.12. HRMS Exact mass calcd. for C23H26ONClF [M + H]+: 386.16815; found: 386.16776.
6-Chloro-2-(4-chlorophenyl)-1-octylquinolin-4(1H)-one (4k). White solid; Yield: 67%; Mp: 92.6–99.2 °C; IR (KBr plate) νmax 2924, 2851, 1616, 1592, 1353, 828, 667. 1H NMR (600 MHz, CDCl3) δ 8.18 (d, J = 2.4 Hz, 1H, CH Ar), 8.08–8.05 (m, 2H, CH Ar), 8.03–8.01 (d, J = 8.9 Hz, 1H, CH Ar), 7.66–7.64 (dd, J = 9.0, 2.4 Hz, 1H, CH Ar), 7.51–7.49 (m, 2H, CH Ar), 7.14 (s, 1H, CH), 4.29–4.27 (t, J = 6.5 Hz, 2H, CH2), 2.02–1.98 (m, 2H, CH2), 1.62–1.57 (p, J = 7.4 Hz, 2H, CH2), 1.48–1.43 (dq, J = 9.3, 6.7 Hz, 2H, CH2), 1.42–1.38 (m, 2H, CH2), 1.36–1.32 (qd, J = 6.5, 2.7 Hz, 4H, CH2), 0.94–0.92 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 161.63 (CO), 157.68, 147.55, 138.38, 135.63, 131.27, 130.90, 130.78, 128.96, 128.78, 121.26, 121.03, 98.72, 68.80, 31.83, 29.33, 29.22, 28.90, 26.13, 22.68, 14.13. HRMS Exact mass calcd. for C23H26ONCl2 [M + H]+: 402.13860; found: 402.13818.
6-Bromo-2-(4-chlorophenyl)-1-octylquinolin-4(1H)-one (4l). White solid; Yield: 75%; Mp: 98.9–100.9 °C; IR (KBr plate) νmax 2924, 2850, 1652, 1557, 1361, 827, 668. 1H NMR (600 MHz, CDCl3) δ 8.35 (d, J = 2.3 Hz, 1H, CH Ar), 8.07–8.05 (m, 2H, CH Ar), 7.95–7.94 (d, J = 8.9 Hz, 1H, CH Ar), 7.79–7.77 (dd, J = 8.9, 2.3 Hz, 1H, CH Ar), 7.51–7.49 (m, 2H, CH Ar), 7.13 (s, 1H, CH), 4.28–4.26 (t, J = 6.5 Hz, 2H, CH2), 2.02–1.97 (m, 2H, CH2), 1.62–1.57 (p, J = 7.2 Hz, 2H, CH2), 1.48–1.43 (m, 2H, CH2), 1.42–1.37 (m, 2H, CH2), 1.37–1.32 (qd, J = 6.5, 2.7 Hz, 4H, CH2), 0.94–0.92 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 161.52 (CO), 157.80, 147.75, 138.36, 135.67, 133.47, 130.90, 128.97, 128.79, 124.34, 121.74, 119.33, 98.72, 68.83, 31.83, 29.33, 29.22, 28.89, 26.12, 22.68, 14.14. HRMS Exact mass calcd. for C23H26ONBrCl [M + H]+: 446.08808; found: 446.08771.
2-(4-Chlorophenyl)-7-methyl-1-octylquinolin-4(1H)-one (4m). Yellow solid; Yield: 76%; Mp: 90.9–93.9 °C; IR (KBr plate) νmax 2965, 2832, 1612, 1593, 1356, 833, 622. 1H NMR (600 MHz, CDCl3) δ 8.12–8.11 (d, J = 8.4 Hz, 1H, CH Ar), 8.08–8.05 (m, 2H, CH Ar), 7.89 (s, 1H, CH Ar), 7.51–7.48 (m, 2H, CH Ar), 7.35–7.33 (dd, J = 8.4, 1.7 Hz, 1H, CH Ar), 7.07 (s, 1H, CH), 4.28–4.26 (t, J = 6.4 Hz, 2H, CH2), 2.58 (s, 3H, CH3), 2.01–1.97 (m, 2H, CH2), 1.62–1.57 (p, J = 7.4 Hz, 2H, CH2), 1.47–1.42 (m, 2H, CH2), 1.41–1.37 (m, 2H, CH2), 1.36–1.32 (m, 4H, CH2), 0.94–0.92 (t, J = 6.9 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.44 (CO), 157.47, 149.45, 140.33, 138.95, 135.25, 128.85, 128.81, 128.24, 127.62, 121.50, 118.45, 97.60, 68.44, 31.83, 29.35, 29.25, 28.98, 26.15, 22.68, 21.82, 14.13. HRMS Exact mass calcd. for C24H29ONCl [M + H]+: 382.19322; found: 382.19247.
7-Fluoro-2-(4-ethylphenyl)-1-octylquinolin-4(1H)-one (4n). Yellow solid; Yield: 66%; Mp: 57.4–60.9 °C; IR (KBr plate) νmax 2967, 2842, 1613, 1598, 1360, 829, 685. 1H NMR (600 MHz, CDCl3) δ 8.21 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.04 (d, J = 8.1 Hz, 2H, CH Ar), 7.73 (dd, J = 10.5, 2.6 Hz, 1H, CH Ar), 7.37 (d, J = 8.0 Hz, 2H, CH Ar), 7.25 (td, J = 8.6, 8.2, 2.5 Hz, 1H, CH Ar), 7.13 (s, 1H, CH), 4.28 (t, J = 6.4 Hz, 2H, CH2), 2.76 (q, J = 7.6 Hz, 2H, CH2), 2.02–1.96 (m, 2H, CH2), 1.60 (p, J = 7.3 Hz, 2H, CH2), 1.48–1.42 (m, 2H, CH2), 1.39 (dd, J = 15.0, 7.2 Hz, 2H, CH2), 1.37–1.33 (m, 4H, CH2), 1.31 (d, J = 7.5 Hz, 3H, CH3), 0.93 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.69 (q, 1JCF = 249.15), 162.27 (CO), 160.20, 150.55 (q, 3JCF = 12.08), 145.94, 137.57, 128.33, 127.58, 124.07 (q, 3JCF = 10.57), 117.41, 115.06 (q, 2JCF = 25.67), 112.76 (q, 2JCF = 19.63), 98.01, 68.54, 31.83, 29.34, 29.25, 28.95, 28.75, 26.15, 22.68, 15.59, 14.12. HRMS Exact mass calcd. for C25H31ONF [M + H]+: 380.23842; found: 380.23761.
6-Chloro-2-(4-ethylphenyl)-1-octylquinolin-4(1H)-one (4o). Yellow solid; Yield: 68%; Mp: 66.6–70.6 °C; IR (KBr plate) νmax 2927, 2856, 1619, 1590, 1365, 824, 635. 1H NMR (600 MHz, CDCl3) δ 8.18–8.17 (d, J = 2.4 Hz, 1H, CH Ar), 8.04–8.02 (dd, J = 8.6, 2.9 Hz, 3H, CH Ar), 7.64–7.63 (dd, J = 8.9, 2.4 Hz, 1H, CH Ar), 7.37–7.36 (d, J = 8.3 Hz, 2H, CH Ar), 7.18 (s, 1H, CH), 4.29–4.27 (t, J = 6.5 Hz, 2H, CH2), 2.77–2.74 (q, J = 7.6 Hz, 2H, CH2), 2.02–1.97 (m, 2H, CH2), 1.62–1.57 (p, J = 7.2 Hz, 2H, CH2), 1.48–1.43 (m, 2H, CH2), 1.42–1.37 (m, 2H, CH2), 1.37–1.33 (ddt, J = 10.0, 6.8, 3.1 Hz, 4H, CH2), 1.33–1.30 (t, J = 7.6 Hz, 3H, CH3), 0.94–0.92 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 161.38 (CO), 159.14, 147.62, 145.91, 137.48, 130.83, 130.73, 130.65, 128.35, 127.52, 121.18, 120.97, 99.04, 68.67, 31.84, 29.34, 29.23, 28.91, 28.74, 26.14, 22.68, 15.58, 14.13. HRMS Exact mass calcd. for C25H31ONCl [M + H]+: 396.20887; found: 396.20831.
6-Bromo-2-(4-ethylphenyl)-1-octylquinolin-4(1H)-one (4p). Yellow solid; Yield: 65%; Mp: 57.2–62.3 °C; IR (KBr plate) νmax 2970, 2864, 1653, 1596, 1366, 843, 682. 1H NMR (600 MHz, CDCl3) δ 8.35 (d, J = 2.3 Hz, 1H, CH Ar), 8.04–8.03 (d, J = 8.3 Hz, 2H, CH Ar), 7.97–7.96 (d, J = 8.9 Hz, 1H, CH Ar), 7.77–7.76 (dd, J = 8.9, 2.3 Hz, 1H, CH Ar), 7.37–7.36 (d, J = 8.2 Hz, 2H, CH Ar), 7.18 (s, 1H, CH), 4.29–4.27 (t, J = 6.5 Hz, 2H, CH2), 2.77–2.73 (q, J = 7.6 Hz, 2H, CH2), 2.02–1.97 (m, 2H, CH2), 1.62–1.57 (p, J = 7.3 Hz, 2H, CH2), 1.48–1.43 (m, 2H, CH2), 1.42–1.37 (m, 2H, CH2), 1.37–1.33 (ddt, J = 9.9, 6.7, 3.2 Hz, 4H, CH2), 1.32–1.30 (t, J = 7.6 Hz, 3H, CH3), 0.94–0.92 (t, J = 6.8 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 161.27 (CO), 159.26, 147.84, 145.95, 137.48, 133.21, 130.89, 128.36, 127.52, 124.27, 121.68, 118.87, 99.03, 68.70, 31.84, 29.34, 29.23, 28.90, 28.75, 26.13, 22.69, 15.58, 14.13. HRMS Exact mass calcd. for C25H31ONBr [M + H]+: 440.15835; found: 440.15790.
7-Methyl-2-(4-ethylphenyl)-1-octylquinolin-4(1H)-one (4q). Yellow solid; Yield: 80%; Mp: 65.9–69.8 °C; IR (KBr plate) νmax 2960, 2854, 1643, 1590, 1359, 853, 652. 1H NMR (600 MHz, CDCl3) δ 8.12–8.10 (d, J = 8.3 Hz, 1H, CH Ar), 8.04–8.02 (m, 2H), CH Ar, 7.90 (s, 1H, CH Ar), 7.37–7.36 (d, J = 8.3 Hz, 2H, CH Ar), 7.33–7.31 (dd, J = 8.4, 1.7 Hz, 1H, CH Ar), 7.11 (s, 1H, CH), 4.29–4.26 (t, J = 6.4 Hz, 2H, CH2), 2.77–2.73 (q, J = 7.6 Hz, 2H, CH2), 2.57 (s, 3H, CH3), 2.01–1.96 (m, 2H, CH2), 1.62–1.57 (p, J = 7.3 Hz, 2H, CH2), 1.47–1.42 (dt, J = 15.0, 6.7 Hz, 2H, CH2), 1.41–1.37 (m, 2H, CH2), 1.36–1.32 (m, 4H, CH2), 1.31–1.28 (d, J = 7.6 Hz, 3H, CH3), δ 1.33–1.30 (t, J = 7.6 Hz, 3H, CH3),0.94–0.92 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 162.20 (CO), 158.91, 149.50, 145.51, 140.03, 138.04, 128.24, 128.22, 127.54, 127.23, 121.45, 118.36, 97.92, 68.33, 31.83, 29.36, 29.26, 29.00, 28.73, 26.16, 22.68, 21.82, 15.62, 14.13. HRMS Exact mass calcd. for C26H34ON [M + H]+: 376.26349; found: 376.26254.
1-Methyl-2-phenylquinolin-4(1H)-one (4r) [66]. Yellow solid; Yield:73 %; Mp: 62.1–64.1 °C; IR (KBr plate) νmax 2987, 2863, 1652, 1591, 1365, 844, 688. 1H NMR (600 MHz, CDCl3) δ 8.23–8.22 (dd, J = 8.3, 1.5 Hz, 1H, CH Ar), 8.15–8.13 (m, 3H, CH Ar), 7.75–7.72 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.56–7.48 (m, 4H, CH Ar), 7.21 (s, 1H, CH), 4.15 (s, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.88 (CO), 158.89, 149.16, 140.39, 130.01, 129.28, 129.18, 128.78, 127.61, 125.43, 121.64, 120.40, 98.04, 55.69. HRMS Exact mass calcd. for C16H14ON [M + H]+: 236.10699; found: 236.10645.
2-(4-Chlorophenyl)-1-methylquinolin-4(1H)-one (4s) [67]. Yellow solid; Yield: 63%; Mp: 109.1–110.9 °C; IR (KBr plate) νmax 2917, 2853, 1652, 1593, 1360, 824, 668. 1H NMR (600 MHz, CDCl3) δ 8.22–8.21 (d, J = 8.2 Hz, 1H, CH Ar), 8.12–8.08 (t, J = 8.6 Hz, 3H, CH Ar), 7.75–7.72 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.53–7.50 (m, 3H, CH Ar), 7.16 (s, 1H, CH), 4.15 (s, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.03 (CO), 157.49, 149.11, 138.74, 135.45, 130.17, 129.14, 128.93, 128.86, 125.62, 121.69, 120.43, 97.59, 55.72. HRMS Exact mass calcd. for C16H13ONCl [M + H]+: 270.06802; found: 270.06750.
2-(4-Ethylphenyl)-1-methylquinolin-4(1H)-one (4t). Colorless oil; Yield: 74%; IR (KBr plate) νmax 2963, 2860, 1683, 1592, 1356, 827, 612. 1H NMR (600 MHz, CDCl3) δ 8.22–8.20 (dd, J = 8.3, 0.9 Hz, 1H, CH Ar), 8.13–8.12 (d, J = 8.2 Hz, 1H, CH Ar), 8.07–8.05 (m, 2H, CH Ar), 7.74–7.71 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.51–7.48 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H, CH Ar), 7.39–7.37 (d, J = 8.5 Hz, 2H, CH Ar), 7.19 (s, 1H, CH), 4.14 (s, 3H, CH3), 2.78–2.74 (q, J = 7.6 Hz, 2H), 1.33–1.30 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 162.77 (CO), 158.92, 149.19, 145.70, 137.85, 129.92, 129.12, 128.32, 127.58, 125.23, 121.61, 120.34, 97.90, 55.64, 28.74, 15.61. HRMS Exact mass calcd. for C18H18ON [M + H]+: 264.13829; found: 264.13763.
7-Fluoro-1-methyl-2-phenylquinolin-4(1H)-one (4u). White solid; Yield: 50 %; Mp: 61.3–63.4 °C; IR (KBr plate) νmax 2970, 2833, 1654, 1590, 1369, 840, 648. 1H NMR (600 MHz, CDCl3) δ 8.21 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.14–8.11 (m, 2H, CH Ar), 7.76–7.74 (dd, J = 10.4, 2.6 Hz, 1H, CH Ar), 7.57–7.54 (m, 2H, CH Ar), 7.51–7.49 (m, 1H, CH Ar), 7.28–7.26 (m, 1H, CH Ar), 7.17 (s, 1H, CH), 4.15 (s, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.77 (q, 1JCF = 249.15), 162.92 (CO), 160.20, 150.45, 140.03, 129.55, 128.82, 127.61, 124.01 (q, 3JCF = 9.06), 117.32, 115.45 (q, 2JCF = 24.16), 112.86 (q, 2JCF = 21.14), 97.60, 55.75. HRMS Exact mass calcd. for C16H13ONF [M + H]+: 254.09757; found: 254.09703.
7-Fluoro-2-(4-ethylphenyl)-1-methylquinolin-4(1H)-one (4v). Yellow solid; Yield: 53%; Mp: 55.2–59.1 °C; IR (KBr plate) νmax 2960, 2843, 1634, 1590, 1359, 850, 628. 1H NMR (600 MHz, CDCl3) δ 8.21–8.18 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.05–8.04 (d, 2H, CH Ar), 7.74–7.72 (dd, J = 10.5, 2.5 Hz, 1H, CH Ar), 7.38–7.37 (d, J = 8.3 Hz, 2H, CH Ar), 7.27–7.24 (ddd, J = 9.1, 8.2, 2.5 Hz, 1H, CH Ar), 7.15 (s, 1H, CH), 4.13 (s, 3H, CH3), 2.78–2.74 (q, J = 7.6 Hz, 2H), 1.33–1.30 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 163.71 (q, 1JCF = 249.15), 162.83 (CO), 160.21, 150.54 (q, 3JCF = 12.08), 146.01, 137.50, 128.36, 127.57, 123.96 (q, 3JCF = 10.57), 117.26, 115.21 (q, 2JCF = 25.67), 112.8 1(q, 2JCF = 19.63), 97.41, 55.70, 28.75, 15.59. HRMS Exact mass calcd. for C18H17ONF [M + H]+: 282.12887; found: 282.12817.
2-(4-Ethylphenyl)-1,7-dimethylquinolin-4(1H)-one (4w). White solid; Yield: 78%; Mp: 86.1–88.3 °C; IR (KBr plate) νmax 2925, 2863, 1625, 1596, 1353, 816, 640. 1H NMR (600 MHz, CDCl3) δ 8.10–8.08 (d, J = 8.4 Hz, 1H, CH Ar), 8.05–8.04 (d, J = 8.2 Hz, 2H, CH Ar), 7.91 (s, 1H, CH Ar), 7.38–7.36 (d, J = 8.1 Hz, 2H, CH Ar), 7.34–7.32 (dd, J = 8.4, 1.7 Hz, 1H, CH Ar), 7.13 (s, 1H, CH), 4.13 (s, 3H, CH3), 2.77–2.74 (q, J = 7.6 Hz, 2H, CH2), 2.58 (s, 3H, CH3), 1.33–1.30 (t, J = 7.6 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.79 (CO), 158.91, 149.43, 145.60, 140.17, 137.92, 128.27, 128.21, 127.54, 127.41, 121.31, 118.21, 97.33, 55.57, 28.73, 21.81, 15.61. HRMS Exact mass calcd. for C19H20ON [M + H]+: 278.15394; found: 278.15338.
2-(4-Chlorophenyl)-1,7-dimethylquinolin-4(1H)-one (4x). Yellow solid; Yield: 73%; Mp: 102.3–104.1 °C; IR (KBr plate) νmax 2921, 2820, 1626, 1595, 1354, 897, 654. 1H NMR (600 MHz, CDCl3) δ 8.11–8.07 (m, 3H, CH Ar), 7.90 (s, 1H, CH Ar), 7.52–7.49 (m, 2H, CH Ar), 7.36–7.34 (dd, J = 8.4, 1.7 Hz, 1H, CH Ar), 7.10 (s, 1H, CH), 4.14 (s, 3H, CH3), 2.58 (s, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.03 (CO), 157.49, 149.37, 140.47, 138.84, 135.34, 128.89, 128.83, 128.23, 127.80, 121.38, 118.30, 97.04, 55.65, 21.82. HRMS Exact mass calcd. for C17H15ONCl [M + H]+: 284.08367; found: 284.08316.
1-Ethyl-2-phenylquinolin-4(1H)-one (4y) [31]. Yellow solid; Yield: 84%; Mp: 101.4–103.6 °C; IR (KBr plate) νmax 2982, 2843, 1613, 1592, 1352, 825, 694. 1H NMR (600 MHz, CDCl3) δ 8.26–8.25 (dd, J = 8.3, 0.9 Hz, 1H, CH Ar), 8.14–8.12 (m, 3H, CH Ar), 7.74–7.72 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.56–7.47 (m, 4H, CH Ar), 7.19 (s, 1H, CH), 4.40–4.36 (q, J = 7.0 Hz, 2H, CH2), 1.65–1.62 (t, J = 7.0 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.16 (CO), 158.88, 149.25, 140.49, 129.93, 129.22, 129.18, 128.76, 127.60, 125.28, 121.77, 120.48, 98.59, 64.10, 14.58. HRMS Exact mass calcd. for C17H16ON [M + H]+: 250.112264; found: 250.12204.
1-Ethyl-2-(4-ethylphenyl)quinolin-4(1H)-one (4z). Yellow solid; Yield: 82%; Mp: 99.8–101.2 °C; IR (KBr plate) νmax 2958, 2865, 1652, 1592, 1353, 821, 640. 1H NMR (600 MHz, CDCl3) δ 8.25–8.23 (dd, J = 8.3, 0.9 Hz, 1H, CH Ar), 8.13–8.12 (d, J = 8.4 Hz, 1H, CH Ar), 8.06–8.04 (m, 2H, CH Ar), 7.73–7.70 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.51–7.48 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H, CH Ar), 7.38–7.37 (d, J = 8.3 Hz, 2H, CH Ar), 7.17 (s, 1H, CH), 4.39–4.35 (q, J = 7.0 Hz, 2H, CH2), 2.78–2.74 (q, J = 7.6 Hz, 2H, CH2), 1.64–1.62 (t, J = 7.0 Hz, 3H, CH3), 1.33–1.30 (t, J = 7.6 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.08 (CO), 158.90, 149.22, 145.65, 137.89, 129.87, 129.07, 128.30, 127.58, 125.11, 121.74, 120.42, 98.46, 64.05, 28.74, 15.62, 14.58. HRMS Exact mass calcd. for C19H20ON [M + H]+: 278.15394; found: 278.15341.
2-(4-Chlorophenyl)-1-ethylquinolin-4(1H)-one (4aa). Yellow solid; Yield: 58%; Mp: 104.3–106.2 °C; IR (KBr plate) νmax 2951, 2834, 1618, 1592, 1359, 834, 641. 1H NMR (600 MHz, CDCl3) δ 8.25–8.24 (d, J = 8.3 Hz, 1H, CH Ar), 8.10–8.07 (t, J = 9.0 Hz, 3H, CH Ar), 7.74–7.72 (t, J = 7.6 Hz, 1H, CH Ar), 7.50–7.50 (d, J = 8.5 Hz, 3H, CH Ar), 7.13 (s, 1H, CH), 4.39–4.35 (q, J = 7.0 Hz, 2H, CH2), 1.64 (t, J = 7.0 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.31 (CO), 157.47, 149.18, 138.83, 135.37, 130.09, 129.14, 128.91, 128.85, 125.48, 121.81, 120.50, 98.13, 64.17, 14.57. HRMS Exact mass calcd. for C17H15ONCl [M + H]+: 284.08367; found: 284.08331.
7-Fluoro-1-ethyl-2-phenylquinolin-4(1H)-one (4ab). Yellow solid; Yield: 56%; Mp: 120.3–124.0 °C; IR (KBr plate) νmax 2970, 2865, 1625, 1593, 1355, 819, 693. 1H NMR (600 MHz, CDCl3) δ 8.25–8.23 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.13–8.09 (m, 2H, CH Ar), 7.75–7.73 (dd, J = 10.5, 2.5 Hz, 1H, CH Ar), 7.56–7.53 (t, J = 7.3 Hz, 2H, CH Ar), 7.50–7.48 (t, J = 7.3 Hz, 1H, CH Ar), 7.28–7.24 (m, 1H, CH Ar), 7.15 (s, 1H, CH), 4.40–4.36 (q, J = 7.0 Hz, 2H, CH2), 1.64–1.62 (t, J = 6.9 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.72 (q, 1JCF = 249.15), 162.23 (CO), 160.18, 150.56 (q, 3JCF = 12.08), 140.14, 129.47, 128.80, 127.60, 124.14(q, 3JCF = 10.57), 117.40, 115.29 (q, 2JCF = 25.67), 112.83(q, 2JCF = 21.14), 98.15, 64.23, 14.55. HRMS Exact mass calcd. for C17H15ONF [M + H]+: 268.11322; found: 268.11258.
7-Fluoro-2-(4-chlorophenyl)-1-ethylquinolin-4(1H)-one (4ac). Yellow solid; Yield: 73%; Mp: 147.8–154.6 °C; IR (KBr plate) νmax 2987, 2864, 1628, 1594, 1353, 813, 680. 1H NMR (600 MHz, CDCl3) δ 8.25–8.22 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.07–8.05 (m, 2H, CH Ar), 7.72–7.70 (dd, J = 10.4, 2.5 Hz, 1H, CH Ar), 7.51–7.49 (m, 2H, CH Ar), 7.28–7.25 (m, 1H, CH Ar), 7.10 (s, 1H, CH), 4.39–4.35 (q, J = 7.0 Hz, 2H, CH2), 1.64–1.62 (t, J = 7.0 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.80 (q, 1JCF = 249.15), 162.41 (CO), 158.77, 150.49 (q, 3JCF = 10.57), 138.44, 135.68, 128.96, 128.86, 124.20 (q, 3JCF = 10.57), 117.43, 115.51 (q, 2JCF = 24.16), 112.78 (q, 2JCF = 21.14), 97.71, 64.31, 14.53. HRMS Exact mass calcd. for C17H14ONClF [M + H]+: 302.07425 found: 302.07376.
7-Fluoro-2-(4-ethylphenyl)-1-ethylquinolin-4(1H)-one (4ad). Yellow solid; Yield: 79%; Mp: 87.4–89.3 °C; IR (KBr plate) νmax 2954, 2874, 1628, 1593, 1355, 817, 648. 1H NMR (600 MHz, CDCl3) δ 8.24–8.21 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.04–8.02 (d, J = 8.2 Hz, 2H, CH Ar), 7.74–7.71 (dd, J = 10.5, 2.5 Hz, 1H, CH Ar), 7.38–7.36 (d, J = 8.0 Hz, 2H, CH Ar), 7.27–7.23 (td, J = 8.6, 2.5 Hz, 1H, CH Ar), 7.13 (s, 1H, CH), 4.38–4.35 (q, J = 7.0 Hz, 2H, CH2), 2.78–2.74 (q, J = 7.6 Hz, 2H, CH2), 1.63–1.61 (t, J = 7.0 Hz, 3H, CH3), 1.33–1.30 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 163.69 (q, 1JCF = 249.15), 162.12 (CO), 160.19, 150.58 (q, 3JCF = 13.59), 145.95, 137.57, 128.34, 127.57, 124.09 (q, 3JCF = 9.06), 117.34, 115.06 (q, 2JCF = 24.16), 112.76 (q, 2JCF = 19.63), 97.98, 64.16, 28.74, 15.59, 14.55. HRMS Exact mass calcd. for C19H19ONF [M + H]+: 296.14352; found: 296.14398.
7-Methyl-2-(4-ethylphenyl)-1-ethylquinolin-4(1H)-one (4ae). Yellow solid; Yield: 82%; Mp: 89.9–94.1 °C; IR (KBr plate) νmax 2965, 2853, 1624, 1505, 1351, 816, 641. 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H, CH Ar), 8.03 (d, J = 8.2 Hz, 2H, CH Ar), 7.90 (s, 1H, CH Ar), 7.36 (d, J = 8.3 Hz, 2H, CH Ar), 7.32 (dd, J = 8.4, 1.7 Hz, 1H, CH Ar), 7.11 (s, 1H, CH), 4.36 (q, J = 7.0 Hz, 2H, CH2), 2.75 (q, J = 7.6 Hz, 2H, CH2), 2.57 (s, 3H, CH3), 1.62 (t, J = 7.0 Hz, 3H), 1.31 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 162.07 (CO), 158.89, 149.49, 145.53, 140.07, 138.02, 128.25, 128.20, 127.53, 127.25, 121.45, 118.30, 97.90, 63.95, 28.73, 21.81, 15.61, 14.59. HRMS Exact mass calcd. for C20H22ON [M + H]+: 292.16959; found: 292.16885.
2-Phenyl-1-propylquinolin-4(1H)-one (4af). Yellow solid; Yield: 78%; Mp: 63.8–69.8 °C; IR (KBr plate) νmax 2963, 2865, 1616, 1592, 1361, 832, 692. 1H NMR (600 MHz, CDCl3) δ 8.27–8.25 (dd, J = 8.2, 1.5 Hz, 1H, CH Ar), 8.14–8.11 (m, 3H, CH Ar), 7.74–7.72 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.56–7.47 (m, 4H, CH Ar), 7.19 (s, 1H, CH), 4.29–4.26 (t, J = 6.4 Hz, 2H, CH2), 2.07–2.01 (h, J = 7.4 Hz, 2H, CH2), 1.21–1.18 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.29 (CO), 158.91, 149.22, 140.49, 129.93, 129.21, 129.16, 128.76, 127.61, 125.28, 121.74, 120.54, 98.64, 69.91, 22.42, 10.69. HRMS Exact mass calcd. for C18H18ON [M + H]+: 264.13829; found: 264.13766.
2-(4-Ethylphenyl)-1-propylquinolin-4(1H)-one (4ag). Yellow solid; Yield: 64%; Mp: 63.6–68.5 °C; IR (KBr plate) νmax 2964, 2836, 1652, 1592, 1360, 825, 668. 1H NMR (600 MHz, CDCl3) δ 8.25–8.24 (dd, J = 8.3, 1.5 Hz, 1H, CH Ar), 8.12–8.11 (d, J = 8.4 Hz, 1H, CH Ar), 8.06–8.04 (d, J = 8.2 Hz, 2H, CH Ar), 7.73–7.70 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.51–7.48 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H, CH Ar), 7.38–7.37 (d, J = 8.3 Hz, 2H, CH Ar), 7.18 (s, 1H, CH), 4.28–4.25 (t, J = 6.4 Hz, 2H, CH2), 2.78–2.74 (q, J = 7.6 Hz, 2H, CH2), 2.06–2.01 (h, J = 7.4 Hz, 2H, CH2), 1.33–1.30 (t, J = 7.6 Hz, 3H, CH3), 1.21–1.18 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.18 (CO), 158.92, 149.25, 145.63, 137.94, 129.84, 129.11, 128.29, 127.57, 125.09, 121.71, 120.49, 98.48, 69.85, 28.74, 22.43, 15.62, 10.69. HRMS Exact mass calcd. for C20H22ON [M + H]+: 292.16959; found: 292.16882.
7-Fluoro-2-phenyl-1-propylquinolin-4(1H)-one (4ah). Yellow solid; Yield: 65%; Mp: 89.5–95.0 °C; IR (KBr plate) νmax 2959, 2858, 1625, 1594, 1364, 816, 689. 1H NMR (600 MHz, CDCl3) δ 8.26–8.23 (dd, J = 9.1, 6.3 Hz, 1H, CH Ar), 8.12–8.11 (m, 2H, CH Ar), 7.75–7.73 (dd, J = 10.5, 2.5 Hz, 1H, CH Ar), 7.56–7.53 (m, 2H, CH Ar), 7.51–7.48 (m, 1H, CH Ar), 7.28–7.25 (m, 1H, CH Ar), 7.16 (s, 1H, CH), 4.28–4.26 (t, J = 6.4 Hz, 2H, CH2), 2.06–2.00 (h, J = 7.4 Hz, 2H, CH2), 1.20–1.18 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.72 (q, 1JCF = 249.15), 162.36 (CO), 160.19, 150.55 (q, 3JCF = 13.59), 140.13, 129.47, 128.80, 127.60, 124.09 (q, 3JCF = 10.57), 117.46, 115.29 (q, 2JCF = 24.16), 112.84 (q, 2JCF = 21.14), 98.18, 70.02, 22.39, 10.66. HRMS Exact mass calcd. for C18H16ONFNa [M + Na]+: 304.11081; found: 304.11011.
7-Fluoro-2-(4-chlorophenyl)-1-propylquinolin-4(1H)-one (4ai). Yellow solid; Yield: 54%; Mp: 93.2–103.9 °C; IR (KBr plate) νmax 2969, 2854, 1622, 1594, 1361, 826, 681. 1H NMR (600 MHz, CDCl3) δ 8.25–8.23 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.08–8.06 (d, J = 8.5 Hz, 2H, CH Ar), 7.72–7.70 (dd, J = 10.3, 2.5 Hz, 1H, CH Ar), 7.51–7.50 (d, J = 8.5 Hz, 2H, CH Ar), 7.28–7.26 (dd, J = 8.6, 2.0 Hz, 1H, CH Ar), 7.11 (s, 1H, CH), 4.27–4.25 (t, J = 6.4 Hz, 2H, CH2), 2.06–2.00 (h, J = 7.1 Hz, 2H, CH2), 1.20–1.18 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.79 (q, 1JCF = 249.15), 162.52 (CO), 158.78, 150.50 (q, 3JCF = 12.08), 138.47, 135.67, 128.95, 128.86, 124.15 (q, 3JCF = 10.57), 117.49, 115.51 (q, 2JCF = 24.16), 112.81 (q, 2JCF = 21.14), 97.75, 70.08, 22.38, 10.65. HRMS Exact mass calcd. for C18H16ONClF [M + H]+: 316.08990; found: 316.08942.
7-Fluoro-2-(4-ethylphenyl)-1-propylquinolin-4(1H)-one (4aj). Yellow solid; Yield: 50%; Mp: 59.3–67.5 °C; IR (KBr plate) νmax 2964, 2881, 1627, 1593, 1361, 820, 667. 1H NMR (600 MHz, CDCl3) δ 8.24–8.21 (dd, J = 9.1, 6.2 Hz, 1H, CH Ar), 8.04–8.03 (d, J = 8.2 Hz, 2H, CH Ar), 7.74–7.72 (dd, J = 10.5, 2.5 Hz, 1H, CH Ar), 7.38–7.36 (d, J = 8.0 Hz, 2H, CH Ar), 7.27–7.23 (td, J = 8.6, 2.6 Hz, 1H, CH Ar), 7.14 (s, 1H, CH), 4.27–4.25 (t, J = 6.4 Hz, 2H, CH2), 2.78–2.74 (q, J = 7.6 Hz, 2H, CH2), 2.06–2.00 (h, J = 7.1 Hz, 2H, CH2), 1.32–1.30 (t, J = 7.6 Hz, 3H, CH3), 1.20–1.17 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 163.39 (q, 1JCF = 249.15), 162.26 (CO), 160.21, 150.59, 145.95, 137.56, 128.33, 127.58, 124.05 (q, 3JCF = 10.57), 117.40, 115.08 (q, 2JCF = 25.67), 112.76 (q, 2JCF = 19.63), 98.02, 69.96, 28.74, 22.39, 15.59, 10.66. HRMS Exact mass calcd. for C20H20ONFNa [M + Na]+: 332.14211; found: 332.14133.
7-Methyl-2-phenyl-1-propylquinolin-4(1H)-one (4ak). Yellow solid; Yield: 77%; Mp: 80.1–82.6 °C; IR (KBr plate) νmax 2925, 2843, 1652, 1594, 1361, 814, 694. 1H NMR (600 MHz, CDCl3) δ 8.14–8.10 (m, 3H, CH Ar), 7.92 (s, 1H, CH Ar), 7.55–7.52 (t, J = 7.5 Hz, 2H, CH Ar), 7.49–7.46 (m, 1H, CH Ar), 7.35–7.33 (dd, J = 8.4, 1.7 Hz, 1H, CH Ar), 7.13 (s, 1H, CH), 4.27–4.25 (t, J = 6.4 Hz, 2H, CH2), 2.58 (s, 3H, CH3), 2.06–2.00 (h, J = 7.4 Hz, 2H, CH2), 1.20–1.17 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.28 (CO), 158.89, 149.49, 140.60, 140.15, 129.11, 128.71, 128.29, 127.57, 127.43, 121.45, 118.42, 98.07, 69.81, 22.43, 21.82, 10.68. HRMS Exact mass calcd. for C19H19ONNa [M + Na]+: 300.13589; found: 300.13525.
7-Methyl-2-(4-ethylphenyl)-1-propylquinolin-4(1H)-one (4al). Yellow solid; Yield: 80%; Mp: 79.0–83.4 °C; IR (KBr plate) νmax 2968, 2820, 1623, 1593, 1356, 816, 665. 1H NMR (600 MHz, CDCl3) δ 8.13–8.11 (d, J = 8.4 Hz, 1H, CH Ar), 8.04–8.03 (d, J = 8.2 Hz, 2H, CH Ar), 7.90 (s, 1H, CH Ar), 7.37–7.36 (d, J = 8.2 Hz, 2H, CH Ar), 7.33–7.31 (dd, J = 8.4, 1.7 Hz, 1H, CH Ar), 7.12 (s, 1H, CH), 4.26–4.24 (t, J = 6.4 Hz, 2H, CH2), 2.77–2.73 (q, J = 7.6 Hz, 2H, CH2), 2.57 (s, 3H, CH3), 2.05–1.99 (h, J = 7.4 Hz, 2H, CH2), 1.32–1,30 (t, J = 7.6 Hz, 3H, CH3), 1.20–1.17 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.18 (CO), 158.91, 149.50, 145.51, 140.04, 138.04, 128.24, 128.22, 127.53, 127.24, 121.42, 118.36, 97.93, 69.76, 28.73, 22.43, 21.82, 15.61, 10.68. HRMS Exact mass calcd. for C21H23ONNa [M + Na]+: 328.16719; found: 328.16669.
2-(4-Eethylphenyl)-1-isopropylquinolin-4(1H)-one (4am). Yellow solid; Yield: 48%; Mp: 86.1–88.3 °C; IR (KBr plate) νmax 2925, 2854, 1652, 1587, 1384, 830, 668. 1H NMR (600 MHz, CDCl3) δ 8.23–8.22 (dd, J = 8.4, 1.5 Hz, 1H, CH Ar), 8.11–8.09 (d, J = 8.3 Hz, 1H, CH Ar), 8.03–8.02 (d, J = 8.1 Hz, 2H, CH Ar), 7.72–7.69 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.49–7.46 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H, CH Ar), 7.38–7.36 (d, J = 8.1 Hz, 2H, CH Ar), 7.17 (s, 1H, CH), 5.00–4.94 (hept, J = 6.1 Hz, 1H, CH), 2.78–2.74 (q, J = 7.6 Hz, 2H, CH2), 1.55–1.54 (d, J = 6.1 Hz, 6H, CH3), 1.33–1.30 (t, J = 7.6 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 161.05 (CO), 158.89, 149.48, 145.58, 135.41, 129.82, 129.07, 128.29, 127.60, 124.97, 121.96, 99.24, 70.58, 28.73, 21.87, 15.62. HRMS Exact mass calcd. for C20H21ONNa [M + Na]+: 314.15154; found: 314.15082.
1-Butyl-2-phenylquinolin-4(1H)-one (4an) [68]. Yellow solid; Yield: 71%; Mp: 75.8–77.8 °C; IR (KBr plate) νmax 2951, 2869, 1621, 1593, 1361, 835, 692. 1H NMR (600 MHz, CDCl3) δ 8.25 (dd, J = 8.3, 1.5 Hz, 1H, CH Ar), 8.13 (dd, J = 7.0, 1.5 Hz, 3H, CH Ar), 7.73 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H, CH Ar), 7.57–7.47 (m, 4H, CH Ar), 7.19 (s, 1H, CH), 4.31 (t, J = 6.4 Hz, 2H, CH2), 2.02–1.97 (m, 2H, CH2), 1.66 (h, J = 7.4 Hz, 2H, CH2), 1.08 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.30 (CO), 158.91, 149.23, 140.50, 129.92, 129.21, 129.17, 128.76, 127.61, 125.28, 121.76, 120.55, 98.62, 68.15, 31.05, 19.40, 13.90. HRMS Exact mass calcd. for C19H19ONNa [M + Na]+: 300.13589; found: 300.13525.
1-Neopentyl-2-phenylquinolin-4(1H)-one (4ao). Yellow solid; Yield: 64%; Mp: 73.8–80.5 °C; IR (KBr plate) νmax 2991, 2899, 1621, 1591, 1365, 825, 642. 1H NMR (600 MHz, CDCl3) δ 8.28–8.26 (d, J = 8.2 Hz, 1H, CH Ar), 8.14–8.12 (dd, J = 7.6, 4.8 Hz, 3H, CH Ar), 7.75–7.72 (m, 1H, CH Ar), 7.56–7.47 (dq, J = 30.1, 7.5 Hz, 4H, CH Ar), 7.18 (s, 1H, CH), 3.94 (s, 2H, CH2), 1.21 (s, 9H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.42 (CO), 158.98, 149.17, 140.45, 129.96, 129.24, 129.17, 128.76, 127.62, 125.33, 121.69, 120.60, 98.65, 32.13, 26.77. HRMS Exact mass calcd. for C20H22ON [M + H]+: 292.16959; found: 292.16916.

3.3. Synthesis of Compounds 4ap–4ar

General procedure. To a solution of DCE (1.5 mL) was added 2-aminoacetophenones 1a (0.37 mmol), benzaldehyde 2a (0.44 mmol), phenols 5 (0.37 mmol), PPA (0.37 mmol) and Pd/C (50 wt%, 19.6 mg, 5 mol% based on Pd content) in a 50 mL round bottom flask. The reaction mixture was refluxed for 3 h. The solution was quenched with water and the organic layer was dried over Na2SO4, filtered and evaporated. The resulting crude compound was purified by silica gel column chromatography using hexane/ethyl acetate mixtures to afford the corresponding products 4ap–4ar.
1,2-Diphenylquinolin-4(1H)-one (4ap). White solid; Yield: 70%; Mp: 69.0–71.2 °C; IR (KBr plate) νmax 1690, 1621, 1593, 1361, 835, 692. 1H NMR (600 MHz, CDCl3) δ 8.39–8.37 (d, J = 8.0 Hz, 1H, CH Ar), 8.20–8.19 (d, J = 8.5 Hz, 1H, CH Ar), 7.98–7,97 (d, J = 7.2 Hz, 2H, CH Ar), 7.81–7.78 (m, 1H, CH Ar), 7.60–7.57 (t, J = 7.6 Hz, 1H, CH Ar), 7.53–7.50 (t, J = 7.9 Hz, 2H, CH Ar), 7.48–7.42 (m, 3H, CH Ar), 7.35–7.33 (t, J = 7.5 Hz, 1H, CH Ar), 7.27–7.26 (d, J = 8.0 Hz, 2H, CH Ar), 7.06 (s, 1H, CH). 13C NMR (151 MHz, CDCl3) δ 162.39 (CO), 158.63, 154.64, 149.82, 139.85, 130.38, 130.34, 129.38, 129.33, 128.72, 127.51, 125.90, 125.50, 121.71, 120.96, 120.61, 102.57. HRMS Exact mass calcd. for C21H16ON [M + H]+: 298.12264; found: 298.12216.
2-Phenyl-1-p-tolyl-quinolin-4(1H)-one (4aq). White solid; Yield: 65%; Mp: 73.3–74.6 °C; IR (KBr plate) νmax 1691, 1651, 1583, 1360, 845, 682. 1H NMR (600 MHz, CDCl3) δ 8.39–8.38 (m, 1H, CH Ar), 8.18–8.19 (d, J = 8.5 Hz, 1H, CH Ar), 7.98–7.96 (m, 2H, CH Ar), 7.80–7.79 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H, CH Ar), 7.59–7.57 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H, CH Ar), 7.48–7.41 (m, 3H, CH Ar), 7.31–7.30 (d, J = 8.1 Hz, 2H, CH Ar), 7.16–7.14 (m, 2H, CH Ar), 7.03 (s, 1H, CH), 2.45 (s, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ 162.73 (CO), 158.66, 152.18, 149.74, 139.94, 135.24, 130.82, 130.33, 129.32, 129.28, 128.69, 127.54, 125.81, 121.74, 120.83, 120.56, 102.18, 20.94. HRMS Exact mass calcd. for C22H18ON [M + H]+: 312.13829; found: 312.13785.
1-(4-Chlorophenyl)-2-phenylquinolin-4(1H)-one (4ar). White solid; Yield: 47%; Mp: 93.9–112.9 °C; IR (KBr plate) νmax 1696, 1631, 1591, 1366, 855, 672. 1H NMR (600 MHz, CDCl3) δ 8.34–8.32 (dd, J = 8.4, 1.5 Hz, 1H, CH Ar), 8.21–8.20 (d, J = 8.5 Hz, 1H, CH Ar), 7.99–7.97 (m, 2H, CH Ar), 7.82–7.99 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H, CH Ar), 7.60–7.58 (m, 1H, CH Ar), 7.50–7.44 (m, 5H, CH Ar), 7.22–7.19 (m, 2H, CH Ar), 7.05 (s, 1H, CH). 13C NMR (151 MHz, CDCl3) δ 162.07 (CO), 158.58, 153.24, 130.77, 130.55, 130.43, 129.49, 129.40, 128.91, 128.79, 128.30, 127.50, 126.08, 122.26, 121.57, 120.44, 102.61. HRMS Exact mass calcd. for C21H15ONCl [M + H]+: 332.08367; found: 332.08319.

3.4. Biological Evaluation

3.4.1. Cell Culture Conditions

Differentiated PC12 cells were cultured in DMEM supplemented with 2.5% fetal bovine serum and and 1% penicillin/streptomycin. Cells were cultured in a humidified atmosphere containing 5% CO2 at 37 °C.

3.4.2. Protective Effects of 4-Quinolones 4a-4ar against NMDA-induced Injury in PC12 Cells

PC12 cells were plated on 96-well plates at a density of 4 × 103 cells/well in 200 μL volumes. After 96 h of incubation, the cells were pretreated with MK-801 and 4-quinolones (20 µM or 0.5–30 µM) for 24 h. NMDA (2 mM) was then added for another 6 h to establish the cell injury model. After these treatments, 0.5 mg/mL MTT was added to the medium. After incubating for an additional 4 h, the medium was replaced by 100 µL DMSO. The absorbance was measured at 490 nm with a microplate reader (Thermo Scientific Varioskan LUX Multimode Reader, Waltham, MA, USA).

3.4.3. Statistical Analysis

Data were expressed as mean ± SD. Multiple group differences were evaluated using one-way analysis of variance (ANOVA) followed by the post hoc LSD test. p < 0.05 were considered statistically significant.

4. Conclusions

In conclusion, we have developed a novel strategy for the synthesis of N-alkyl-4-quinolones via mechanistically intriguing three-component tandem reactions of 2-aminoacetophenones, aldehydes and alcohols. Our work provided the first proof of PPE as a dual hydrogen-bonding catalyst. Notable advantages of this protocol include readily accessible reagents, a one-pot procedure, broad substrate scope and being transition-metal free. The neuroprotective activity evaluation showed that compound 4h demonstrated good protective potency.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28052304/s1, Figure S1: 31P NMR analysis of the PPE-7 complex; Figure S2: protective effects of 4-quinolones on NMDA toxicity; Figure S3: docking of compound 4h with glycine binding site of NMDA receptor; Table S1: optimization studies for the synthesis of 4-quinolone 4a; Table S2: optimization studies for the synthesis of 1-phenyl-4-quinolone 4ap; copies of the 1H-NMR and 13C-NMR spectra for all compounds [69,70,71,72,73].

Author Contributions

H.L. (Huanhuan Liu): investigation, methodology and biological evaluation; H.L. (Huadan Liu): investigation, methodology; E.W. and Z.L.: data curation, formal analysis; L.L. and J.C. (Jiafu Cao): data curation; J.C. (Jialin Chen): DFT calculation; L.Y. and X.Y.: funding acquisition, project administration, writing—original draft, writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (No. 32160104), the Project of Guizhou Science and Technology Platform and Talent Team (No. QKHZC (2021) general 424 and QKHZC (2021) general 129), the Guizhou Provincial Natural Science Foundation (No. QKHJC (2021) general 512), the Project of Key Laboratory for Characteristics of Colleges and Universities of Guizhou Provincial Department of Education (No. QJHKYZ (2020)018).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We are grateful to the staff at the Key Laboratory of Chemistry for Natural Products of Guizhou Province and the Chinese Academy of Sciences.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Fort, D.M.; Litvak, J.; Chen, J.L.; Lu, Q.; Phuan, P.W.; Cooper, R.; Bierer, D.E. Isolation and unambiguous synthesis of cryptolepinone: An oxidation artifact of cryptolepine. J. Nat. Prod. 1998, 61, 1528–1530. [Google Scholar] [CrossRef] [PubMed]
  2. Koyama, J.; Toyokuni, I.; Tagahara, K. Synthesis of 2-arylquinoline and 2-aryl-4-quinolone alkaloids via Diels-Alder reaction of 1,2,3-benzotriazine with enamines. Chem. Pharm. Bull. 1999, 47, 1029–1038. [Google Scholar] [CrossRef] [Green Version]
  3. Krishnamurthy, M.; Gooch, B.D.; Beal, P.A. Peptide quinoline conjugates: A new class of RNA-binding molecules. Org. Lett. 2004, 6, 63–66. [Google Scholar] [CrossRef] [PubMed]
  4. Haddad, N.; Tan, J.; Farina, V. Convergent synthesis of the quinolone substructure of biln 2061 via carbonylative sonogashira coupling/cyclization. J. Org. Chem. 2006, 71, 5031–5034. [Google Scholar] [CrossRef] [PubMed]
  5. Krishnamurthy, M.; Simon, K.; Orendt, A.M.; Beal, P.A. Macrocyclic helix-threading peptides for targeting RNA. Angew. Chem. Int. Ed. 2007, 46, 7044–7047. [Google Scholar] [CrossRef] [PubMed]
  6. Hadjeri, M.; Mariotte, A.M.; Boumendjel, A. Alkylation of 2-phenyl-4-quinolones: Synthetic and structural studies. Chem. Pharm. Bull. 2001, 49, 1352–1355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Xia, Y.; Yang, Z.Y.; Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J.H.; Lee, K.H. Antitumor agents. 211. fluorinated 2-phenyl-4-quinolone derivatives as antimitotic antitumor agents. J. Med. Chem. 2001, 44, 3932–3936. [Google Scholar] [CrossRef]
  8. Hadjeri, M.; Peiller, E.L.; Beney, C.; Deka, N.; Lawson, M.A.; Dumontet, C.; Boumendjel, A. Antimitotic activity of 5-hydroxy-7-methoxy-2-phenyl-4-quinolones. J. Med. Chem. 2004, 47, 4964–4970. [Google Scholar] [CrossRef]
  9. Lucero, B.A.; Gomes, C.R.B.; Frugulhetti, I.C.D.P.P.; Faro, L.V.; Alvarenga, L.; Souza, M.C.B.V.; de Souza, T.M.L.; Ferreira, V.F. Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues. Bioorg. Med. Chem. Lett. 2006, 16, 1010–1013. [Google Scholar] [CrossRef]
  10. Santo, R.D.; Costi, R.; Roux, A.; Artico, M.; Lavecchia, A.; Marinelli, L.; Novellino, E.; Palmisano, L.; Andreotti, M.; Amici, R.; et al. Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: Design, synthesis, biological activities, and mechanism of action. J. Med. Chem. 2006, 49, 1939–1945. [Google Scholar] [CrossRef] [Green Version]
  11. Kuo, S.; Lee, H.; Juang, J.; Lin, Y.; Wu, T.; Chang, J.; Lednicer, D.; Paull, K.D.; Lin, C.; Hamel, E.; et al. Synthesis and cytotoxicity of 1,6,7,8-substituted 2-(4′-substituted phenyl)-4-quinolones and related compounds: Identification as antimitotic agents interacting with tubulin. J. Med. Chem. 1993, 36, 1146–1156. [Google Scholar] [CrossRef] [PubMed]
  12. Llinas-Brunet, M.; Bailey, M.D.; Ghiro, E.; Gorys, V.; Halmos, T.; Poirier, M.; Rancourt, J.; Goudreau, N. A systematic approach to the optimization of substrate-based inhibitors of the hepatitis C virus NS3 protease: Discovery of potent and specific tripeptide inhibitors. J. Med. Chem. 2004, 47, 6584–6594. [Google Scholar] [CrossRef] [PubMed]
  13. Nakamura, S.; Kozuka, M.; Bastow, K.F.; Tokuda, H.; Nishino, H.; Suzuki, M.; Tatsuzaki, J.; Natschke, S.L.M.; Kuo, S.C.; Lee, K.H. Cancer preventive agents, part 2: Synthesis and evaluation of 2-phenyl-4-quinolone and 9-oxo-9,10-dihydroacridine derivatives as novel antitumor promoters. Bioorg. Med. Chem. 2005, 13, 4396–4401. [Google Scholar] [CrossRef] [PubMed]
  14. Reitsema, R.H. The chemistry of 4-hydroxyquinolines. Chem. Rev. 1948, 43, 43–68. [Google Scholar] [CrossRef] [PubMed]
  15. Brouet, J.C.; Gu, S.; Peet, N.P.; Williams, J.D. Survey of solvents for the conrad-limpach synthesis of 4-hydroxyquinolones. Synthetic Commun. 2009, 39, 1563–1569. [Google Scholar] [CrossRef] [PubMed]
  16. Romek, A.; Opatz, T. Microwave-assisted synthesis of polysubstituted 4-quinolones from deprotonated α-aminonitriles. Eur. J. Org. Chem. 2010, 30, 5841–5849. [Google Scholar] [CrossRef]
  17. Zewge, D.; Chen, C.Y.; Deer, C.; Dormer, P.G.; Hughes, D.L. A mild and efficient synthesis of 4-quinolones and quinolone heterocycles. J. Org. Chem. 2007, 72, 4276–4279. [Google Scholar] [CrossRef]
  18. Niementowski, S. Synthesen der chinolinderivate. Ber. Dtsch. Chem. Ges. 1894, 27, 1394–1403. [Google Scholar] [CrossRef] [Green Version]
  19. Fuson, R.C.; Burness, D.M. A new synthesis of 2-aryl-4-hydroxyquinolines. J. Am. Chem. Soc. 1946, 68, 1270–1272. [Google Scholar] [CrossRef]
  20. Ogata, Y.; Kawasaki, A.; Tsujimura, K. Kinetics and mechanism of the formation of 4-hydroxyquinoline from methyl anthranilate. Tetrahedron 1971, 27, 2765–2770. [Google Scholar] [CrossRef]
  21. Son, J.K.; Kim, S.I.; Jahng, Y. A modified niementowski reaction for the synthesis of 4-hydroxyquinoline and its related compounds. Heterocycles 2001, 55, 1981–1986. [Google Scholar]
  22. Camps, R. Synthese von α-und γ-oxychinolinen. Arch. Pharm. 1899, 237, 659–691. [Google Scholar] [CrossRef] [Green Version]
  23. Jones, C.P.; Anderson, K.W.; Buchwald, S.L. Sequential Cu-catalyzed amidation-base-mediated camps cyclization: A two-step synthesis of 2-aryl-4-quinolones from o-halophenones. J. Org. Chem. 2007, 72, 7968–7973. [Google Scholar] [CrossRef] [PubMed]
  24. Huang, J.; Chen, Y.; King, A.O.; Dilmeghani, M.; Larsen, R.D.; Faul, M.M. A mild, one-pot synthesis of 4-quinolones via sequential Pd-catalyzed amidation and base-promoted cyclization. Org. Lett. 2008, 10, 2609–2612. [Google Scholar] [CrossRef]
  25. Deng, Y.; Gong, W.; He, J.; Yu, J.Q. Ligand-enabled triple C-H activation reactions: One-pot synthesis of diverse 4-aryl-2-quinolinones from propionamides. Angew. Chem. Int. Ed. 2014, 53, 6810–6813. [Google Scholar] [CrossRef]
  26. Torii, S.; Okumoto, H.; Xu, L.H. Palladium-catalyzed carbonylation to form 2-substituted 1, 4-dihydro-4-oxo-quinoline. Tetrahedron Lett. 1991, 32, 237–240. [Google Scholar] [CrossRef]
  27. Seppanen, O.; Muuronen, M.; Helaja, J. Gold-catalyzed conversion of aryl- and alkyl-substituted 1-(o-aminophenyl)-2-propyn-1-ones to the corresponding 2-substituted 4-quinolones. Eur. J. Org. Chem. 2014, 2014, 4044–4052. [Google Scholar] [CrossRef]
  28. Zhao, T.K.; Xu, B. Palladium-catalyzed tandem amination reaction for the synthesis of 4-quinolones. Org. Lett. 2010, 12, 212–215. [Google Scholar] [CrossRef]
  29. Åkerbladh, L.; Nordeman, P.; Wejdemar, M.; Odell, L.R.; Larhed, M. Synthesis of 4-quinolones via a carbonylative sonogashira cross-coupling using molybdenum hexacarbonyl as a CO source. J. Org. Chem. 2015, 80, 1464–1471. [Google Scholar] [CrossRef]
  30. Fei, X.; Zhou, Z.; Li, W.; Zhu, Y.; Shen, J. Buchwald-hartwig coupling/michael addition reactions: One-pot synthesis of 1,2-disubstituted 4-quinolones from chalcones and primary amines. Eur. J. Org. Chem. 2012, 2012, 3001–3008. [Google Scholar] [CrossRef]
  31. Xu, X.; Zhang, X. Direct synthesis of 4-quinolones via copper-catalyzed anilines and alkynes. Org. Lett. 2017, 19, 4984–4987. [Google Scholar] [CrossRef] [PubMed]
  32. Shao, J.; Huang, X.M.; Hong, X.H.; Liu, B.X.; Xu, B. Synthesis of N-akyl-substituted 4-quinolones via tandem alkenyl and aryl C-N bond formation. Synthesis 2012, 44, 1798–1805. [Google Scholar]
  33. Iaroshenko, V.O.; Mkrtchyan, S.; Villinger, A. Efficient [5+1] synthesis of 4-quinolones by domino amination and conjugate addition reactions of 1-(2-fluorophenyl)prop-2-yn-1-ones with amines. Synthesis 2013, 45, 205–218. [Google Scholar] [CrossRef]
  34. Okamoto, N.; Takeda, K.; Ishikura, M.; Yanada, R. One-pot approach to 2,3-disubstituted-2,3-dihydro-4-quinolones from 2-alkynylbenzamides. J. Org. Chem. 2011, 76, 9139–9143. [Google Scholar] [CrossRef] [PubMed]
  35. Hu, W.; Lin, J.; Song, L.; Long, Y. Direct synthesis of 2-aryl-4-quinolones via transition-metal-free intramolecular oxidative C (sp3)-H/C (sp3)-H coupling. Org. Lett. 2015, 17, 1268–1271. [Google Scholar] [CrossRef] [PubMed]
  36. Ma, H.; Guo, C.; Zhan, Z.; Lu, G.; Zhang, Y.; Luo, X.; Huang, G. Transition-metal-free oxidative intermolecular cyclization reaction: Synthesis of 2-aryl-4-quinolones. New J. Chem. 2017, 41, 5280–5283. [Google Scholar] [CrossRef]
  37. Doyle, A.G.; Jacobsen, E.N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 2007, 107, 5713–5743. [Google Scholar] [CrossRef]
  38. Gondi, V.B.; Gravel, M.; Rawal, V.H. Hydrogen bond catalyzed enantioselective vinylogous mukaiyama aldol reaction. Org. Lett. 2015, 7, 5657–5660. [Google Scholar] [CrossRef] [Green Version]
  39. Grayson, M.N.; Yang, Z.; Houk, K.N. Chronology of CH…O hydrogen bonding from molecular dynamics studies of the phosphoric acid-catalyzed allylboration of benzaldehyde. J. Am. Chem. Soc. 2017, 139, 7717–7720. [Google Scholar] [CrossRef] [Green Version]
  40. Connon, S.J. Organocatalysis mediated by (thio) urea derivatives. Chem. Eur. J. 2006, 12, 5418–5427. [Google Scholar] [CrossRef]
  41. Taylor, M.S.; Jacobsen, E.N. Asymmetric catalysis by chiral hydrogen-bond donors. Angew. Chem. Int. Ed. 2006, 45, 1043–1520. [Google Scholar] [CrossRef] [PubMed]
  42. Connon, S.J. Chiral phosphoric acids: Powerful organocatalysts for asymmetric addition reactions to imines. Angew. Chem. Int. Ed. 2006, 45, 3909–3912. [Google Scholar] [CrossRef] [PubMed]
  43. Marccelli, T.; van Maarseveen, J.H.; Hiemstra, H. Cupreines and cupreidines: An emerging class of bifunctional cinchona organocatalysts. Angew. Chem. Int. Ed. 2006, 45, 7496–7504. [Google Scholar] [CrossRef] [PubMed]
  44. Sigman, M.S.; Jacobsen, E.N. Schiff base catalysts for the asymmetric Strecker reaction identified and optimized from parallel synthetic libraries. J. Am. Chem. Soc. 1998, 120, 4901–4902. [Google Scholar] [CrossRef]
  45. Vachal, P.; Jacobsen, E.N. Structure-based analysis and optimization of a highly enantioselective catalyst for the Strecker reaction. J. Am. Chem. Soc. 2002, 124, 10012–10014. [Google Scholar] [CrossRef] [PubMed]
  46. List, B.; Lerner, R.A.; Barbas, C.F. Proline-catalyzed direct asymmetric aldol reactions. J. Am. Chem. Soc. 2000, 122, 2395–2396. [Google Scholar] [CrossRef]
  47. Tang, Z.; Jiang, F.; Yu, L.T.; Cui, X.; Gong, L.Z.; Mi, A.Q.; Jiang, Y.Z.; Wu, Y.D. Novel small organic molecules for a highly enantioselective direct aldol reaction. J. Am. Chem. Soc. 2003, 125, 5262–5263. [Google Scholar] [CrossRef]
  48. Rajaram, S.; Sigman, M.S. Design of hydrogen bond catalysts based on a modular oxazoline template: Application to an enantioselective hetero Diels-Alder reaction. Org. Lett. 2005, 7, 5375–5473. [Google Scholar] [CrossRef]
  49. Yang, K.; Lou, Y.; Wang, C.; Qi, L.W.; Fang, T.; Zhang, F.; Song, Q. Chiral brønsted acid from chiral phosphoric acid boron complex and water: Asymmetric reduction of indoles. Angew. Chem. 2020, 132, 3320–3325. [Google Scholar] [CrossRef]
  50. Rajkumar, S.; Tang, M.; Yang, X. Chiral phosphoric acid catalyzed kinetic resolution of 2-amido benzyl alcohols: Asymmetric synthesis of 4H-3,1-benzoxazines. Angew. Chem. 2020, 132, 2353–2357. [Google Scholar] [CrossRef]
  51. Ermanis, K.; Colgan, A.C.; Proctor, R.S.; Hadrys, B.W.; Phipps, R.J.; Goodman, J.M. A computational and experimental investigation of the origin of selectivity in the chiral phosphoric acid catalyzed enantioselective minisci reaction. J. Am. Chem. Soc. 2020, 142, 21091–21101. [Google Scholar] [CrossRef] [PubMed]
  52. Ishihara, H.; Huang, J.; Mochizuki, T.; Hatano, M.; Ishihara, K. Enantio- and diastereoselective carbonyl-ene Cyclization-acetalization tandem reaction catalyzed by tris(pentafluorophenyl) borane-assisted chiral phosphoric acids. ACS Catal. 2021, 11, 6121–6127. [Google Scholar] [CrossRef]
  53. Mukherjee, S.; List, B. Chiral counteranions in asymmetric transition-metal catalysis: Highly enantioselective Pd/Brønsted acid-catalyzed direct α-allylation of aldehydes. J. Am. Chem. Soc. 2007, 129, 11336–11337. [Google Scholar] [CrossRef] [PubMed]
  54. Tran, V.T.; Nimmagadda, S.K.; Liu, M.; Engle, K.M. Recent applications of chiral phosphoric acids in palladium catalysis. Org. Biomol. Chem. 2020, 18, 618–637. [Google Scholar] [CrossRef]
  55. Zhou, F.; Yamamoto, H. A powerful chiral phosphoric acid catalyst for enantioselective Mukaiyama-Mannich reactions. Angew. Chem. 2016, 128, 9116–9120. [Google Scholar] [CrossRef]
  56. Zhang, L.; Wu, B.; Chen, Z.; Hu, J.; Zeng, X.; Zhong, G. Chiral phosphoric acid catalyzed enantioselective N-alkylation of indoles with in situ generated cyclic N-acyl ketimines. Chem. Commun. 2018, 54, 9230–9233. [Google Scholar] [CrossRef]
  57. Zhu, Y.; He, W.; Wang, W.; Pitsch, P.E.; Wang, X.; Wang, X. Enantioselective tandem cyclization of alkyne-tethered indoles using cooperative silver (I)/chiral phosphoric acid catalysis. Angew. Chem. 2017, 129, 12374–12377. [Google Scholar] [CrossRef]
  58. Kanaoka, Y.; Miyashita, K.; Yonemttsu, O. 3H-Indoles-II: Synthesis of 3-alkyl-3H-indoles by the alkylation of 2,3-disubstituted indoles with polyphosphate ester and some reactions of the 3H-indole system. Terahedron 1969, 25, 2757–2766. [Google Scholar] [CrossRef]
  59. Yang, L.; Wang, E.; Fan, Y.; Yang, J.; Luo, Z.; Wang, Y.; Peng, M.; Deng, T.; Yang, X. One-pot synthesis of (E)-3-benzylideneflavanones from 2-hydroxyacetophenones and aromatic aldehydes. Tetrahedron Lett. 2020, 61, 151180–151181. [Google Scholar] [CrossRef]
  60. Wang, E.; Yang, L.; Yang, Q.; Yang, F.; Luo, J.; Gan, M.; Wang, X.; Song, S.; Lei, Y.; Yang, X. Polyphosphoric acid-promoted one-pot synthesis and neuroprotective effects of flavanones against NMDA-induced injury in PC12 cells. RSC Adv. 2022, 12, 28098–28103. [Google Scholar] [CrossRef]
  61. Gaunt, M.J.; Spencer, J.B. Derailing the wacker oxidation: Development of a palladium-catalyzed amidation reaction. Org. Lett. 2000, 3, 25–28. [Google Scholar] [CrossRef]
  62. Tan, B.; Lu, Y.; Zeng, X.; Chua, P.J.; Zhong, G. Facile domino access to chiral bicyclo[3.2.1]octanes and discovery of a new catalytic activation mode. Org. Lett. 2010, 12, 2682–2685. [Google Scholar] [CrossRef]
  63. Zhu, B.; Zhang, W.; Richmond, L.; Han, Z.; Yang, W.; Tan, D.; Huang, K.W.; Jiang, Z. Direct asymmetric vinylogous aldol reaction of allyl ketones with isatins: Divergent synthesis of 3-hydroxy-2-oxindole derivatives. Angew. Chem. Int. Ed. 2013, 125, 6798–6802. [Google Scholar] [CrossRef]
  64. Cordi, A.A.; Desos, P.; Randle, J.C.R.; Lepagnol, J. Structure-activity relationships in a series of 3-sulfonylamino-2-(1H)-quinolones as new AMPA/kainate and glycine antagonists. Bioorg. Med. Chem. 1995, 3, 129–141. [Google Scholar] [CrossRef] [PubMed]
  65. Desos, P.; Lepagnol, J.M.; Morain, P.; Lestage, P.; Cordi, A.A. Structure-activity relationships in a series of 2(1H)-quinolones bearing different acidic function in the 3-position: 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid, a new potent and selective AMPA/kainate antagonist with neuroprotective properties. J. Med. Chem. 1996, 39, 197–206. [Google Scholar] [CrossRef] [PubMed]
  66. Song, Y.J.; Choi, J.S.; Lee, J.I. An efficient synthesis of 1-alkyl-2-phenyl-4-quinolones from 2-halobenzoic acids. Bull. Korean Chem. Soc. 2013, 34, 3117–3120. [Google Scholar] [CrossRef] [Green Version]
  67. Klier, L.; Bresser, T.; Nigst, T.A.; Karaghiosoff, K.; Knochel, P. Lewis acid-triggered selective zincation of chromones, quinolones, and thiochromones: Application to the preparation of natural flavones and isoflavones. J. Am. Chem. Soc. 2012, 134, 13584–13587. [Google Scholar] [CrossRef]
  68. Wang, D.; Sun, P.; Jia, P.; Peng, J.; Yue, Y.; Chen, C. Transition-metal-free one-pot tandem synthesis of 4-quinolone and 4H-thiochromen-4-one derivatives through sequential nucleophilic addition-elimination-SNAr reaction. Synthesis 2017, 49, 4309–4320. [Google Scholar]
  69. Zhao, Y.; Truhlar, D.G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, ex-cited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Account. 2008, 120, 215–241. [Google Scholar]
  70. Ochterski, J.W.; Petersson, G.A.; Montgomery, J.A., Jr. A complete basis set model chemistry. V. Extensions to six or more heavy atoms. J. Chem. Phys. 1996, 104, 2598–2619. [Google Scholar]
  71. Grisafi, A.; Wilkins, D.M.; Csányi, G.; Ceriotti, M. Symmetry-adapted machine learning for tensorial properties of atomistic systems. Phys. Rev. Lett. 2018, 120, 036002. [Google Scholar]
  72. Lu, T.; Chen, Q. van der Waals potential: An important complement to molecular electrostatic potential in studying intermolecular interactions. J. Mol. Model. 2020, 26, 315. [Google Scholar]
  73. Peterson, K.I.; Pullman, D.P. Determining the structure of oxalate anion using infrared and Raman spectroscopy coupled with Gaussian calculations. J. Chem. Educ. 2016, 93, 1130–1133. [Google Scholar]
Molecules 28 02304 g001 550
Figure 1. Selected bioactive 4-quinolone derivatives.
Figure 1. Selected bioactive 4-quinolone derivatives.
Molecules 28 02304 g001
Molecules 28 02304 sch001 550
Scheme 1. Procedures for the synthesis of 4-quinolones. (a) Synthesis of 4-quinolones. (b) Three-component tandem reactions for the synthesis of N-alkyl-4-quinolones.
Scheme 1. Procedures for the synthesis of 4-quinolones. (a) Synthesis of 4-quinolones. (b) Three-component tandem reactions for the synthesis of N-alkyl-4-quinolones.
Molecules 28 02304 sch001
Molecules 28 02304 sch002 550
Scheme 2. Experimental and computational mechanistic investigations. (a) Synthesis of N-alkyl-4-quinolone via three-component tandem reaction. (b) Control experiments. (c) DFT calculations.
Scheme 2. Experimental and computational mechanistic investigations. (a) Synthesis of N-alkyl-4-quinolone via three-component tandem reaction. (b) Control experiments. (c) DFT calculations.
Molecules 28 02304 sch002
Molecules 28 02304 sch003 550
Scheme 3. Experimental mechanistic investigations. Reactivity of phosphates (a) and chalcones (b–d).
Scheme 3. Experimental mechanistic investigations. Reactivity of phosphates (a) and chalcones (b–d).
Molecules 28 02304 sch003
Molecules 28 02304 g002 550
Figure 2. Concentration-dependent protective effects of 4h. Data are presented as mean ± SD (n = 3). MK-801 was used as positive control. ### p < 0.001 as compared to control group, * p < 0.05, ** p < 0.01, *** p < 0.001 as compared to NMDA group.
Figure 2. Concentration-dependent protective effects of 4h. Data are presented as mean ± SD (n = 3). MK-801 was used as positive control. ### p < 0.001 as compared to control group, * p < 0.05, ** p < 0.01, *** p < 0.001 as compared to NMDA group.
Molecules 28 02304 g002
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 28 02304 i001
EntryAdditiveSolvent4a (%) b
1P2O5 DMF69
2 cPPA/P2O5 DMF58
3PPA DMA50
4PPA acetone24
5PPA CH3CN63
6PPA DCM56
7PPA toluene29
8PPA etherND
9PPA4 Å MSDMF78
10 dPPA DMF70
a Reaction conditions: 1a (0.37 mmol), 2a (0.44 mmol), 3a (1 mL), solvent (0.5 mL). b Isolated yield. c PPA (0.5 equiv.), P2O5 (0.5 equiv.). d Reaction conditions: 1a (7.4 mmol), 2a (8.88 mmol), 3a (6 mL), DMF (3 mL). ND referred to “not detected”.
Table
Table 2. Evaluation of substrate scope a,b.
Table 2. Evaluation of substrate scope a,b.
Molecules 28 02304 i002
Molecules 28 02304 i003
a Reaction conditions: 1 (0.37 mmol), 2 (0.44 mmol), 3 (1 mL), PPA (0.37 mmol), DMF (0.5 mL). b Isolated yield.
Table
Table 3. Scope of phenols a,b.
Table 3. Scope of phenols a,b.
Molecules 28 02304 i004
Molecules 28 02304 i005
a Reaction conditions: 1 (0.37 mmol), 2a (0.44 mmol), 5 (0.44 mmol), PPA (0.37 mmol), Pd/C (5 mol%), DCE (1.5 mL). b Isolated yield.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Liu, H.; Liu, H.; Wang, E.; Li, L.; Luo, Z.; Cao, J.; Chen, J.; Yang, L.; Yang, X. Hydrogen Bond Assisted Three-Component Tandem Reactions to Access N-Alkyl-4-Quinolones. Molecules 2023, 28, 2304. https://doi.org/10.3390/molecules28052304

AMA Style

Liu H, Liu H, Wang E, Li L, Luo Z, Cao J, Chen J, Yang L, Yang X. Hydrogen Bond Assisted Three-Component Tandem Reactions to Access N-Alkyl-4-Quinolones. Molecules. 2023; 28(5):2304. https://doi.org/10.3390/molecules28052304

Chicago/Turabian Style

Liu, Huanhuan, Huadan Liu, Enhua Wang, Liangqun Li, Zhongsheng Luo, Jiafu Cao, Jialin Chen, Lishou Yang, and Xiaosheng Yang. 2023. "Hydrogen Bond Assisted Three-Component Tandem Reactions to Access N-Alkyl-4-Quinolones" Molecules 28, no. 5: 2304. https://doi.org/10.3390/molecules28052304

Article Metrics

Back to TopTop