Cationic Pd(II) catalyzed regioselective intramolecular hydroarylation for the efficient synthesis of 4-aryl-2-quinolones

Tetrahedron 75 (2019) 2506e2520

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Cationic Pd(II) catalyzed regioselective intramolecular hydroarylation for the efficient synthesis of 4-aryl-2-quinolones Karandeep Singh a, b, Bhanwar Kumar Malviya a, Ved Prakash Verma c, Satpal Singh Badsara d, Vimal K. Bhardwaj e, Siddharth Sharma a, * a

Department of Chemistry, Mohanlal Sukhadia University, Udaipur, 313001, India Department of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar, 143005, India Department of Chemistry, Banasthali University, Newai-Jodhpuriya Road, Vanasthali, 304022, India d MFOS Laboratory, Department of Chemistry (Centre of Advanced Study), University of Rajasthan, JLN Marg, Jaipur, 302004, India e Department of Chemistry, National Institute of Technology Jalandhar, 144011, India b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 January 2019 Received in revised form 11 March 2019 Accepted 14 March 2019 Available online 20 March 2019

A divergent regioselective palladium (II) catalyzed approach through post Ugi cyclization is described. The Ugi adduct underwent intramolecular ortho-hydroarylation via 6-endo-dig cyclization for the direct access to 4-aryl-2-quinolones. Incorporation of iodine at the C-3 position of 2-quinolone followed by Suzuki-Miyaura coupling results into the more diversified 3,4-diaryl-2-quinolones. © 2019 Elsevier Ltd. All rights reserved.

Keywords: Multi-component reaction Ugi reaction Isocyanide Hydroarylation Cyclization Palladium catalyst

1. Introduction Quinolone is a versatile component of many biologically, pharmaceutically and agro-chemically active compounds [1]. A vast number of pharmaceuticals containing these skeletons are being used for therapeutic purposes. Recently, It has been reported for their bioactivities such as a kinase inhibitors, amyloid b fibrogenesis inhibitors, anti-hepatitis B virus agents, and maxi-K channel openers, which have made quinolone very captivated in recent years (Fig. 1) [2]. This prevalence of quinolone moiety in medicinal chemistry demands to introduce mandatory functionalities with diverse molecular frameworks that could met the potency of small drug like molecules. Despite, several promising reports for the construction of quinolone scaffolds, the diversity remains a nontrivial challenge [3]. In this context, multicomponent reactions (MCRs) have been emerged as powerful tool because of rapid converging strategy, one

* Corresponding author. E-mail addresses: [email protected], [email protected] (S. Sharma). https://doi.org/10.1016/j.tet.2019.03.026 0040-4020/© 2019 Elsevier Ltd. All rights reserved.

pot procedure, affording high yields and easy access to active biological heterocycles in a single step [4]. Most significantly, combinatorial libraries of compounds along with the maximum diversity could be generated via MCRs (Scheme 1) [5]. Among MCRs, Ugi reaction has great contributions, whilst coupled with post Ugi condensations [6], provided enormous new synthetic opportunities just by tethering the suitable functionalities in the starting components of Ugi reaction, inaccessible by other methods. The pioneering work has established by Armstrong in post Ugi modifications by employing the convertible isocyanides (1Cyclohexen-1-yl isocyanide) marked renaissance in synthetic domain [7]. Within the span of few years, Erik group has established wide range of gold catalyzed post Ugi modifications for the preparation of diverse heterocycles from Ugi adduct containing tethered alkynes [8]. The interesting fact is that the comparatively similar or same starting material may have different mode of annulations, with variant mechanism, led to the distinct scaffold. For example, the comparatively similar Ugi adduct, afforded distinct products (Scheme 1) via post Ugi cyclization under different catalytic conditions [9,10]. More recently, our research group designed the regioselective

K. Singh et al. / Tetrahedron 75 (2019) 2506e2520

Fig. 1. Selected examples of 2-quinolones based bio-active molecules.

Scheme 1. Synthesis of different products from comparative similar substrate using Ugi reaction.

synthesis of two heterocycles benzoxazepinones and benzoxazinones from the same Ugi adduct, underwent post Ugi transformations through different modes of cyclization when subjected to palladium and gold catalyst respectively [11]. In addition, the very nature of post Ugi modifications; there are still many hidden chemical spaces to explore which may led to novel synthetic routes for biologically active compounds. By utilizing the similar Ugi adduct 5, we endeavored to construct a highly regioselective distinct heterocycle via hydroarylation. So, following our ongoing research to synthesize new heterocycles via IMCRs [12], we herein report the Pd catalyzed intramolecular 6-endo-dig ortho-hydroarylation of Ugi adduct 5 derived through methoxylated anilines to afford the N-substituted 4-aryl 2-quinolone 6 with high regioselectivity in moderate to good yield (Fig. 2). 2. Result and discussion From the literature survey, it was found that Ugi adduct 5 derived from para alkoxy aniline experienced dearomative ipso spirocyclization [9,10]. We commenced our investigation, keeping in mind to switch off dearomative ipso spirocyclization of the Ugi adduct 5 and switch on regioselective 6-endo-dig ortho-

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hydroarylation to synthesize 4-aryl-2-quinolone heterocycle (6). Cyclization precursor N-(3,4,5-trimethoxyphenyl)propiolamide 5a was achieved in good yield via usual [13] Ugi four component reaction (U-4CR) of p-methylbenzaldehyde (1) with 3,4,5trimethoxyaniline (2), 3-phenylpropiolic acid (3) and tert-butyl isonitrile (4) in methanol at room temperature. Next, to affirm the hypothesis and to optimize the reaction conditions, the cyclization precursor 5a as a model substrate was subjected to the different catalytic conditions (Table 1) for the synthesis of 6a. Initial efforts aiming to do hydroarylation was by performing the reaction of 5a in the absence of transition metals, using solely Brønsted acids such as triflic acid and PPA (Table 1, entry 1, 2) as catalyst, did not yield any product in 12 h. Next, switching to the Lewis acid catalyst AlCl3 in
DCE at 50 C though resulted into regioselective hydroarylated product 6 as a sole regioisomer in moderate yield (Table 1, entry 3), but Ugi adduct 5a was remained unreacted on TLC. To assure the formation of requisite product 6a, reaction mixture was then separated by column chromatography and characterized by NMR spectroscopy. 28% Product was formed when the reaction was carried out with AgNO3 (Table 1, entry 4). Evaluation of several Pd(II) catalysts, afforded the product 6a with isolated yield in the range of 15e48%, (Table 1, entry 5e7). To our delight, the sharp increase upto 83% yield was observed (Table 1, entry 8) when cationic Pd catalyst Pd(CH3CN)4(BF4)2 (10 mol%) catalyst in DCE at
50 C for 12 h was used. Further increase the amount of Pd(CH3CN)4(BF4)2 catalyst in DCE did not make significant improvement in the yield (Table 1, entry 9). Though, lowering the Pd catalyst significantly decreased the yield to 27% (Table 1, entry 10) and no effect was observed when the reaction temperature was raised to 80
C (Table 1, entry 16). In particular, DCE discovered to be the best solvent amid different solvents used such as toluene, CH3CN, DMF and DCM in terms of yield b Table 1, entries 12, 13 and 15). In order to verify the scope and generality of optimized reaction conditions, a wide range of diversified library of Ugi adducts were synthesized (Table 2, entries 5a-5g0 ) and integrated with Pdcatalyzed 6-endo-dig ortho-hydroarylation. To our delight, maximum reactions performed well, afforded 4-aryl-2-quinolones (Table 2, 6a-6g0 ) in good yields. Incorporation of different aromatic substituents (having electron donating and electron withdrawing groups) on the alkyne moiety in the Ugi adduct showed remarkable tolerance for the quinolone scaffold irrespective of steric effects (Table 2, entries 6a-6d). On the other hand, the Ugi adducts with aliphatic and terminal alkyne substituent's (R ¼ Me, H) also worked for ortho-hydroarylation under standard conditions specifically with combination of tert-butyl isonitrile afforded products (Table 2, entries 6e-6f) albeit in moderate yields. The reaction of same substituents (R ¼ Me, H) but with alternative isonitriles provided no product. Next, to evaluate the cogency of this method, several isocyanides derivatives were employed in the Ugi adduct (Table 2, entries 5a, 5g-5j) generated cyclised adducts (Table 2, entries 6a, 6g-6j) in moderate to good yields. The effect of aromatic aldehydes, exhibiting both electron withdrawing and electron donating groups has been examined for this transformation, found to be well tolerated on aldehyde derived Ugi adduct delivered the desired product in good to excellent yields. In comparison to electron withdrawing groups i.e trifluoromethane (6s), chloro (6o), cyano (6p), flouro (6n,6r), bromo (6q), the electron donating groups methoxy (6l), methyl (6a), benzyloxy (6m), provided better yields for ortho-hydroarylation. The presence of bulky group such as benzyloxy (6m) at the aldehyde site did not affect the yield of the hydroarylated product. As derivatization at aniline component, the Ugi adduct derived from 3,4,5-trimethoxy and 3,5-dimethoxy aniline were found to be well tolerated, acted as electron rich centres for nucleophilic attack at the alkyne moiety via ortho-

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Fig. 2. Divergent synthetic approach to 4-aryl-2-quinolone via MCRs.

hydroarylation, delivering benzene annulated quinolone in good to excellent yields. Heteroaromatic alkynoic acid such as 3-(pyridin-4-yl)propiolic acid (10) were attempted by the Sonogashira reaction for the synthesis, however yields was very poor (<20%) hence, we didn't perform the Ugi reaction with the heteroaromatic substituents. A plausible mechanism has been depicted in Scheme 2 for the Pd(CH3CN)4(BF4)2 catalyzed synthesis of 4-aryl-2-quinolones via ortho-hydroarylation. Firstly, formation of Pd(II) in situ coordinated the alkyne moiety, and thus activated it for the attack of nucleophile, generated the intermediate A. The electron rich ortho position of phenyl ring of aniline with three methoxy groups in the Ugi adduct served as a nucleophile and attack at the activated alkyne in a 6-endo-dig fashion instead of 5-exo-dig, resulted into regioselective intramolecular hydroarylation, to afford dearomatized intermediate B. Further, the positive charge thus formed on the adjacent carbon was resonance stabilized by the lone pair of nitrogen atom and/or methoxy groups present on the benzene ring to generate the intermediate B [1] and C. Finally, the loss of proton followed by the protodepalladation lead to the rearomatized

quinolone scaffold 6k. Further, an attempt was made to cleave the N-acetamide group of 6a under strong acidic conditions such as TFA and conc. H2SO4 resulted into the removal of tert-butyl group and dealkylated product 7 was isolated in 56% of yield (Scheme 3). Next, hydroarylated products (Scheme 4, 6g-6p) were subjected to iodination at C-3 position, using previously reported conditions [14], and afforded 8 (Scheme 4, 8a, 8b) in good yields (82e86%). Further, these iodination products underwent Suzuki-Miyaura coupling [15] with boronic acids for the formation of more diversified quinolones 9 (Scheme 4, 9a-9b) with arylation at the Csp2-3 carbon in good yields (61e74%). Finally, it is interesting to note that when Ugi adduct derived from aniline subjected to the standard reaction conditions for ortho-hydroarylation, generated substituted a-amino amides (6aa6ac) (Scheme 5) in moderate to good yields (53e63%). These results indicate that, an electron donating group on the aniline component is prerequisite for the hydroarylation reaction. Moreover, this efficient method to remove acid component may be useful for the protection and deprotection sequence of secondary amines.

Table 1 Optimization of hydroarylation conditions for the synthesis of product 6a.a

Entry

Catalyst (mol%)

Solvent

Yield (%)

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

TfOH (100) PPA (104)b AlCl3 AgNO3 Pd(OAc)2 PdCl2 Pd(OCOCF3)2 Pd(CH3CN)4(BF4)2 Pd(CH3CN)4(BF4)2 Pd(CH3CN)4(BF4)2 Pd(CH3CN)4(BF4)2 Pd(CH3CN)4(BF4)2 Pd(CH3CN)4(BF4)2 Pd(CH3CN)4(BF4)2 Pd(CH3CN)4(BF4)2 Pd(CH3CN)4(BF4)2

DCM e DCM DCE DCE DCE DCE DCE DCE DCE DCE CH3CN Toluene DMF DCM DCM

0 0 34 28 15 15 48 83 82 27 39 52 36 53 63 82

a b c d

(10) (20) (5) (10) (10) (10) (10) (10) (10)

Reaction conditions: 5a (1 mmol), the catalyst were heated at 50
C in 5 ml of solvent for 12 h. Temperature of the reaction was 100
C for 6 h. Reaction temperature was 30
C DCE. Temperature of the reaction was 80
C for 12 h.: 1,2-dichloroethane, DCM: dichloromethane, DMF: dimethylformamide.

K. Singh et al. / Tetrahedron 75 (2019) 2506e2520 Table 2 Substrate scope of ortho-hydroarylation of Ugi adduct to form the quinolinones.a

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Scheme 5. Unexpected cleavage of acid component using aniline in Ugi adduct.

3. Conclusion In conclusion, a Pd catalyzed highly regioselective 6-endo-dig ortho-hydroarylation of Ugi adduct was achieved by employing the Ugi reaction. A variety of complex quinolone derivatives were assembled in good to excellent yields. In addition, this approach assured the broad substrate scope, diversity of product and well tolerance to functional groups. Moreover, additional synthesis of substituted a-amino amides has been demonstrated under slandered condition. 4. Experimental section4.1. Materials and methods

Scheme 2. Plausible mechanism for the quinolone synthesis via ortho-hydroarylation.

Scheme 3. Attempt for the N-deacetamidation of 6a.

All reactions were carried out in oven- or flame-dried glassware unless otherwise noted. Except as otherwise indicated, all reactions were magnetically stirred and monitored by analytical thin layer chromatography (TLC) using precoated silica gel glass plates (0.25 mm) with a F254 indicator. Visualization was accomplished by UV light (254 nm). Flash column chromatography was performed using silica gel (100e200 mesh). Yields refer to pure compounds, unless otherwise noted. Commercial grade reagents and solvents were used without further purification. 1H and 13C NMR spectra were recorded on a Bruker 400 and 500 MHz NMR spectrometer using CDCl3 as a solvent for deuterium locking, with temperature at 298 K. Chemical shifts are given in parts per million with TMS as an internal reference. J values are given in hertz. 13C NMR spectra were recorded as solutions in CDCl3 with complete proton decoupling, 13C {1H NMR}. Mass spectra were recorded on a Bruker MicroTOF Q II mass spectrometer. The solutions were made/ diluted in acetonitrile/H2O (3:7) and directly injected to the ESI

Scheme 4. Synthesis of diversified quinolone 9 using Suzuki-Miyaura coupling.

K. Singh et al. / Tetrahedron 75 (2019) 2506e2520

source through a pump. 4.2. General procedure for the Ugi adduct synthesis (5a-5g0 ) In a round-bottam flask, a solution of amine (1 mmol) in methanol (5 mL) were added successively aldehyde (1.0 equiv), acid (1.0 equiv), and isonitrile (1.0 equiv), equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature for 12e24 h in round-bottom flask. After completion the reaction, solid was precipitate and separated by filtration. Solid was washed with ether and used without further purification. 4.3. General procedure for the synthesis of 4-aryl-2-quinolone (6a6g0 ) using Pd(CH3CN)4(BF4)2 catalyst To a screw capped dry glass vial equipped with a magnetic stir bar added Ugi product (5a-g′) (0.2 mmol) and Pd(CH3CN)4(BF4)2 (10 mol %) along with DCE (2 mL). The reaction vial was evacuated, backfilled with nitrogen, and was stirred at 50
C in oil bath for 12 h. After completion the reaction, solvent was evaporated under reduced pressure. The crude obtained was directly purified by silica gel column chromatography (10e20% EtOAc in hexane) without workup to afford pure compounds. 4.3.1. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-3-phenyl-N(3,4,5-trimethoxyphenyl)propiolamide (5a) Synthesis of 5a was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.55; yielded a white solid (406 mg, 1 mmol, 79% yield). 1H NMR (500 MHz, CDCl3) d 1.34 (s, 9H), 2.29 (s, 3H), 3.66 (s, 6H), 3.82 (s, 3H), 5.56 (s, 1H), 5.98 (s, 1H), 6.46 (s, 2H), 7.03e7.11 (m, 6H), 7.20 (t, J ¼ 6.4 Hz, 2H), 7.29 (t, J ¼ 6.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 21.3, 28.6, 51.7, 56.2, 60.9, 65.0, 82.6, 91.7, 108.6, 120.4, 128.3, 129.1, 130.0, 130.3, 131.3, 132.5, 135.2, 137.9, 138.5, 152.5, 154.9, 167.9; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H34N2O5 537.2360; found 537.2369. 4.3.2. N-(tert-butyl)-2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4phenylquinolin-1(2H)-yl)acetamide (6a) Synthesis of 6a was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.65; yielded a pale yellow solid (427 mg, 1 mmol, 83% yield). 1H NMR (500 MHz, CDCl3) d 1.34 (s, 9H), 2.32 (s, 3H), 3.21 (s, 3H), 3.64 (s, 3H), 3.74 (s, 3H), 6.24 (s, 1H), 6.43 (s, 1H), 6.93 (s, 1H), 6.98 (s, 1H), 7.12 (d, J ¼ 8.5 Hz, 2H), 7.24 (s, 1H), 7.34e7.41 (m, 6H); 13 C NMR (125 MHz, CDCl3) d 21.0, 28.6, 51.7, 55.9, 60.7, 60.8, 65.0, 97.7, 109.7, 119.8, 127.1, 127.2, 127.4, 129.2, 131.6, 136.6, 137.2, 138.1, 141.1, 150.9, 151.0, 155.2, 162.4, 167.6; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H34N2O5 537.2360; found 537.2368. 4.3.3. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-3-(p-tolyl)N-(3,4,5-trimethoxyphenyl)propiolamide (5b) Synthesis of 5b was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.58; yielded a pale white solid (433 mg, 1 mmol, 82% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.29 (s, 6H), 3.65 (s, 6H), 3.82 (s, 3H), 5.59 (s, 1H), 5.98 (s, 1H), 6.46e6.48 (m, 2H), 6.98e7.10 (m, 8H); 13C NMR (100 MHz, CDCl3) d 21.2, 21.6, 28.6, 51.6, 56.1, 60.9, 65.0, 82.3, 92.2, 108.6, 117.3, 129.1, 130.3, 131.4, 132.4, 135.3, 137.9, 138.5, 140.6, 152.5, 155.1, 168.0; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H36N2O5 551.2516; found 551.2521. 4.3.4. N-(tert-butyl)-2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4-(ptolyl)quinolin-1(2H)-yl)acetamide (6b) Synthesis of 6b was achieved according to the general procedure

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and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.67; yielded a pale yellow solid (354 mg, 1 mmol, 67% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.32 (s, 3H), 2.41 (s, 3H), 3.23 (s, 3H), 3.64 (s, 3H), 3.74 (s, 3H), 6.27 (s, 1H), 6.44 (s, 1H), 6.93e6.98 (m, 2H), 7.12e7.14 (m, 2H), 7.21e7.24 (m, 5H), 7.48 (d, J ¼ 20.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.1, 21.3, 28.6, 51.7, 55.9, 60.9, 97.7, 109.9, 114.0, 119.8, 127.4, 127.9, 129.2, 131.5, 136.8, 137.3, 138.1, 138.2, 151.1, 151.2, 155.2, 162.5, 167.6; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H36N2O5 551.2516; found 551.2509. 4.3.5. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-3-(4methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)propiolamide (5c) Synthesis of 5c was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.52; yielded a white solid (424 mg, 1 mmol, 78% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.29 (s, 3H), 3.66 (s, 6H), 3.76 (s, 3H), 3.82 (s, 3H), 5.60 (s, 1H), 5.98 (s, 1H), 6.45 (s, 2H), 6.72 (d, J ¼ 8.0 Hz, 2H), 7.03e7.10 (m, 6H); 13C NMR (100 MHz, CDCl3) d 21.2, 28.7, 51.7, 55.4, 56.2, 61.0, 65.0, 82.1, 92.5, 108.6, 112.3, 114.1, 129.2, 130.4, 131.5, 134.4, 135.5, 137.9, 138.5, 152.5, 155.3, 161.0, 168.1; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H36N2O6 567.2466; found 567.2479. 4.3.6. N-(tert-butyl)-2-(p-tolyl)-2-(5,6,7-trimethoxy-4-(4methoxyphenyl)-2-oxoquinolin-1(2H)-yl)acetamide (6c) Synthesis of 6c was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.60; yielded a pale yellow solid (386 mg, 1 mmol, 71% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.32 (s, 3H), 3.24 (s, 3H), 3.63 (s, 3H), 3.75 (s, 3H), 3.87 (s, 3H), 6.25 (s, 1H), 6.44 (s, 1H), 6.92e6.94 (m, 3H), 6.98 (s, 1H), 7.11 (d, J ¼ 8.0 Hz, 2H), 7.23 (d, J ¼ 8.0 Hz, 2H), 7.29 (d, J ¼ 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.7, 51.7, 55.3, 56.0, 61.0, 77.8, 109.9, 112.7, 120.0, 127.5, 128.9, 129.2, 131.6, 133.4, 136.8, 137.3, 138.3, 150.8, 151.2, 159.0, 162.5, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H36N2O6 567.2466; found 567.2478. 4.3.7. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-3-(4fluorophenyl)-N-(3,4,5-trimethoxyphenyl)propiolamide (5d) Synthesis of 5d was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.51; yielded a white solid (410 mg, 1 mmol, 77% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.29 (s, 3H), 3.66 (s, 6H), 3.81 (s, 3H), 5.53 (s, 1H), 5.98 (s, 1H), 6.45 (s, 2H), 6.89 (t, J ¼ 8.4 Hz, 2H), 7.03e7.11 (m, 6H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.6, 51.7, 56.1, 60.9, 65.0, 82.4, 90.6, 108.5, 115.7, 115.9, 116.5, 129.1, 130.3, 131.2, 134.5, 134.6, 135.2, 137.9, 138.6, 152.5, 154.8, 162.2, 164.7, 167.9; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H33FN2O5 555.2266; found 555.2273. 4.3.8. N-(tert-butyl)-2-(4-(4-fluorophenyl)-5,6,7-trimethoxy-2oxoquinolin-1(2H)-yl)-2-(p-tolyl)acetamide (6d) Synthesis of 6d was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.57; yielded a pale yellow solid (420 mg, 1 mmol, 79% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.32 (s, 3H), 3.24 (s, 3H), 3.64 (s, 3H), 3.75 (s, 3H), 6.22 (s, 1H), 6.42 (s, 1H), 6.93 (s, 1H), 6.96 (s, 1H), 7.07 (t, J ¼ 8.8 Hz, 2H), 7.12 (d, J ¼ 8.0 Hz, 2H), 7.24 (d, J ¼ 8.0 Hz, 2H), 7.31e7.34 (m, 2H); 13C NMR (100 MHz, CDCl3) d 21.0, 28.6, 51.7, 55.9, 60.7, 60.9, 97.7, 109.5, 114.1, 114.3, 120.1, 127.4, 129.2, 131.5, 136.7, 136.9, 137.3, 138.1, 149.8, 150.9, 155.3, 160.8, 162.2, 163.3, 167.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H33FN2O5 555.2266; found 555.2269.

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4.3.9. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-N-(3,4,5trimethoxyphenyl)but-2-ynamide (5e) Synthesis of 5e was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.59; yielded a white solid (307 mg, 1 mmol, 68% yield). 1H NMR (400 MHz, CDCl3) d 1.32 (s, 9H), 1.74 (s, 3H), 2.28 (s, 3H), 3.66 (s, 6H), 3.80 (s, 3H), 5.52 (s, 1H), 5.91 (s, 1H), 6.36 (s, 2H), 7.02 (s, 4H); 13C NMR (100 MHz, CDCl3) d 21.1, 27.7, 28.6, 51.2, 51.6, 56.1, 60.9, 65.0, 74.0, 90.8, 108.3, 129.0, 130.2, 130.3, 135.1, 137.7, 138.4, 152.4, 154.9, 168.0; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C26H32N2O5 475.2203; found 475.2216. 4.3.10. N-(tert-butyl)-2-(p-tolyl)-2-(5,6,7-trimethoxy-4-methyl-2oxoquinolin-1(2H)-yl)acetamide (6e) Synthesis of 6e was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.68; yielded a pale yellow solid (330 mg, 1 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) d 1.30 (s, 9H), 2.30 (s, 3H), 2.66 (s, 3H), 3.60 (s, 3H), 3.81 (s, 3H), 3.93 (s, 3H), 6.17 (s, 1H), 6.45 (d, J ¼ 0.4 Hz, 1H), 6.85 (s, 1H), 7.01 (s, 1H), 7.07 (d, J ¼ 8.0 Hz, 2H), 7.15 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.0, 23.7, 28.5, 51.6, 55.9, 60.8, 61.2, 97.9, 110.7, 118.9, 127.3, 129.0, 131.3, 136.2, 137.0, 138.1, 148.7, 151.8, 154.6, 162.6, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C26H32N2O5 475.2203; found 475.2212. 4.3.11. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-N-(3,4,5trimethoxyphenyl)propiolamide (5f) Synthesis of 5f was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.56; yielded a white solid (324 mg, 1 mmol, 74% yield). 1H NMR (400 MHz, CDCl3) d 1.32 (s, 9H), 2.28 (s, 3H), 2.87 (s, 1H), 3.66 (s, 6H), 3.80 (s, 3H), 5.46 (s, 1H), 5.92 (s, 1H), 6.21e6.38 (m, 2H), 6.99e7.04 (m, 4H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.5, 51.7, 56.0, 60.9, 65.0, 76.2, 80.2, 108.3, 129.1, 130.3, 131.0, 134.3, 138.0, 138.6, 152.4, 153.6, 167.6; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C25H30N2O5 461.2047; found 461.2140. 4.3.12. N-(tert-butyl)-2-(p-tolyl)-2-(5,6,7-trimethoxy-2oxoquinolin-1(2H)-yl)acetamide (6f) Synthesis of 6f was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.66; yielded a pale yellow solid (280 mg, 1 mmol, 64% yield). 1H NMR (400 MHz, CDCl3) d 1.31 (s, 9H), 2.30 (s, 3H), 3.61 (s, 3H), 3.83 (s, 3H), 4.01 (s, 3H), 6.10 (s, 1H), 6.62 (d, J ¼ 9.6 Hz, 1H), 6.78 (s, 1H), 6.98 (s, 1H), 7.09 (d, J ¼ 8 Hz, 2H), 7.17 (d, J ¼ 8.4 Hz, 2H), 8.03 (d, J ¼ 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.0, 28.6, 51.6, 56.0, 61.0, 61.7, 97.1, 110.0, 117.2, 127.4, 129.1, 131.4, 134.6, 136.1, 137.0, 137.2, 149.1, 155.5, 163.3, 167.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C25H30N2O5 461.2047; found 461.2043. 4.3.13. N-(2-(cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-3-phenylN-(3,4,5-trimethoxyphenyl)propiolamide (5g) Synthesis of 5g was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.50; yielded a white solid (394 mg, 1 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) d 1.01e1.18 (m, 3H), 1.29e1.40 (m, 2H), 1.57e1.69 (m, 3H), 1.85 (d, J ¼ 12.4 Hz, 1H), 1.94 (d, J ¼ 10 Hz, 1H), 2.30 (s, 3H), 3.66 (s, 6H), 3.82 (s, 3H), 3.83e3.87 (m, 1H), 5.54 (d, J ¼ 8 Hz, 1H), 6.03 (s, 1H), 6.49 (s, 2H), 7.04 (d, J ¼ 8 Hz, 2H), 7.09e7.12 (m, 4H), 7.20 (t, J ¼ 7.6 Hz, 2H), 7.30 (tt, J ¼ 7.6 Hz, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.1, 24.7, 24.8, 25.4, 32.8, 32.9, 48.8, 56.1, 60.9, 64.7, 82.5, 91.7, 108.5, 120.3, 128.3, 129.2, 130.0, 130.2, 131.1, 132.5, 135.3, 137.8, 138.6, 152.5, 155.0, 168.0; HRMS (ESITOF) m/z [M þ K]þ calcd for C33H36N2O5 579.2256; found 579.2217.

4.3.14. N-cyclohexyl-2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4phenylquinolin-1(2H)-yl)acetamide (6g) Synthesis of 6g was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.63; yielded a pale yellow solid (427 mg, 1 mmol, 79% yield). 1H NMR (400 MHz, CDCl3) d 1.05e1.25 (m, 3H), 1.29e1.39 (m, 2H), 1.58 (s, 1H), 1.69 (s, 2H), 1.76 (d, J ¼ 11.6 Hz, 1H), 1.98 (d, J ¼ 9.2 Hz, 1H), 2.32 (s, 3H), 3.20 (s, 3H), 3.62 (s, 3H), 3.73 (s, 3H), 3.78e3.88 (m, 1H), 6.40 (d, J ¼ 8 Hz, 1H), 6.43 (s, 1H), 6.99 (s, 1H), 7.02 (s, 1H), 7.12 (d, J ¼ 8 Hz, 2H), 7.26e7.28 (m, 2H), 7.32e7.39 (m, 5H); 13C NMR (100 MHz, CDCl3) d 21.0, 24.6, 25.4, 32.5, 32.8, 48.6, 55.9, 60.7, 60.8, 97.8, 109.8, 119.7, 127.1, 127.3, 129.3, 131.6, 136.5, 137.3, 138.2, 141.1, 151.0, 151.1, 155.2, 162.4, 167.4; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C33H36N2O5 563.2516; found 563.2529. 4.3.15. N-(2-oxo-1-(p-tolyl)-2-((2,4,4-trimethylpentan-2-yl) amino)ethyl)-3-phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5 h) Synthesis of 5h was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.55; yielded a white solid (433 mg, 1 mmol, 76% yield). 1H NMR (400 MHz, CDCl3) d 0.91 (s, 9H), 1.39 (s, 3H), 1.44 (s, 3H), 1.55 (d, J ¼ 14.8 Hz, 1H), 1.73 (d, J ¼ 14.8 Hz, 1H), 2.30 (s, 3H), 3.67 (s, 6H), 3.83 (s, 3H), 5.59 (s, 1H), 5.90 (s, 1H), 6.47 (s, 2H), 7.04e7.12 (m, 6H), 7.20 (t, J ¼ 7.2 Hz, 2H), 7.30 (t, J ¼ 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.4, 28.8, 31.4, 31.5, 52.6, 55.7, 56.2, 60.9, 65.7, 82.6, 91.7, 108.3, 120.4, 128.3, 129.1, 130.0, 130.3, 131.3, 132.5, 135.6, 137.9, 138.5, 152.5, 154.8, 167.4; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C35H42N2O5 593.2986; found 593.2988. 4.3.16. 2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4-phenylquinolin1(2H)-yl)-N-(2,4,4-trimethylpentan-2-yl)acetamide (6 h) Synthesis of 6h was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.69; yielded a pale yellow solid (439 mg, 1 mmol, 77% yield). 1H NMR (400 MHz, CDCl3) d 0.81 (s, 9H), 1.40 (s, 6H), 1.60 (d, J ¼ 15.2 Hz, 2H), 2.32 (s, 3H), 3.21 (s, 3H), 3.63 (s, 3H), 3.63 (s, 3H), 3.74 (s, 1H), 6.17 (s, 1H), 6.45 (s, 1H), 6.90 (s, 1H), 7.07 (s, 1H), 7.12 (d, J ¼ 8.4 Hz, 2H), 7.26 (s, 1H), 7.28 (s, 1H), 7.34e7.42 (m, 5H); 13C NMR (100 MHz, CDCl3) d 21.0, 28.2, 29.0, 31.2, 31.4, 52.5, 55.6, 56.0, 60.8, 60.9, 109.6, 119.6, 127.1, 127.3, 127.6, 129.1, 131.2, 137.1, 138.1, 141.1, 150.9, 151.1, 155.3, 162.2, 167.1; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C35H42N2O5 593.2986; found 593.2985. 4.3.17. N-(2-oxo-2-(pentylamino)-1-(p-tolyl)ethyl)-3-phenyl-N(3,4,5-trimethoxyphenyl)propiolamide (5i) Synthesis of 5i was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.53; yielded a white solid (438 mg, 1 mmol, 83% yield). 1H NMR (400 MHz, CDCl3) d 0.84 (t, J ¼ 7.2 Hz, 3H), 1.20e1.32 (m, 4H), 1.44e1.52 (m, 2H), 2.30 (s, 3H), 3.25 (q, J ¼ 6.4 Hz, 13.6 Hz, 2H), 3.67 (s, 6H), 3.82 (s, 3H), 5.69 (t, J ¼ 5.2 Hz, 1H), 6.03 (s, 1H), 6.49 (s, 2H), 7.04 (d, J ¼ 8 Hz, 2H), 7.10 (d, J ¼ 8.4 Hz, 4H), 7.20 (t, J ¼ 7.2 Hz, 2H), 7.30 (tt, J ¼ 7.6 Hz, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 13.9, 21.1, 22.2, 28.9, 29.1, 39.9, 56.1, 60.9, 64.8, 82.5, 91.7, 108.5, 120.3, 128.3, 129.2, 130.0, 130.3, 131.1, 132.5, 135.3, 137.8, 138.7, 152.5, 154.9, 168.8; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H36N2O5 551.2516; found 551.2531. 4.3.18. N-pentyl-2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4phenylquinolin-1(2H)-yl)acetamide (6i) Synthesis of 6i was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.50; yielded a pale yellow solid (428 mg, 1 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) d 0.81 (t, J ¼ 7.2 Hz, 3H),

K. Singh et al. / Tetrahedron 75 (2019) 2506e2520

1.18e1.329 (m, 4H), 1.45e1.53 (m, 2H), 2.33 (s, 3H), 3.20 (s, 3H), 3.26e3.32 (m, 2H), 3.62 (s, 3H), 3.73 (s, 3H), 6.44 (s, 1H), 6.52 (t, J ¼ 5.6 Hz, 1H), 6.97 (s, 1H), 7.08 (s, 1H), 7.13 (d, J ¼ 8.4 Hz, 2H), 7.26e7.29 (m, 2H), 7.33e7.42 m, 5H); 13C NMR (100 MHz, CDCl3) d 13.9, 21.0, 22.2, 28.9, 29.0, 39.7, 55.9, 60.8, 60.9, 97.8, 109.8, 127.1, 127.3, 129.2, 131.4, 136.4, 137.3, 138.2, 141.1, 151.10, 151.12, 155.2, 162.4, 168.3; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H36N2O5 551.2516; found 551.2522.

4.3.19. N-(2-((butyryloxy)amino)-2-oxo-1-(p-tolyl)ethyl)-3phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5j) Synthesis of 5j was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (50% EtOAc/ Hexane) 0.53; yielded a white solid (462 mg, 1 mmol, 85% yield). 1H NMR (400 MHz, CDCl3) d 1.24 (t, J ¼ 7.2 Hz, 3H), 2.29 (s, 3H), 3.66 (s, 6H), 3.82 (s, 3H), 4.07 (d, J ¼ 5.2 Hz, 2H), 4.15 (q, J ¼ 7.2 Hz, 14.8 Hz, 2H), 6.18 (s, 1H), 6.32 (s, 1H), 6.46 (s, 2H), 7.05 (d, J ¼ 7.6 Hz, 2H), 7.10 (t, J ¼ 7.6 Hz, 4H), 7.20 (t, J ¼ 7.6 Hz, 2H), 7.30 (t, J ¼ 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 14.1, 21.4, 41.6, 56.1, 60.9, 61.5, 64.4, 82.4, 91.9, 108.5, 120.3, 128.3, 129.2, 130.1, 130.5, 132.5, 135.0, 137.9, 138.8, 152.6, 155.0, 169.2, 169.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H32N2O7 567.2102; found 567.2102. 4.3.20. N-(butyryloxy)-2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4phenylquinolin-1(2H)-yl)acetamide (6j) Synthesis of 6j was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.53; yielded a pale yellow solid (337 mg, 1 mmol, 62% yield). 1H NMR (400 MHz, CDCl3) d 1.21 (t, J ¼ 7.2 Hz, 3H), 2.33 (s, 3H), 3.20 (s, 3H), 3.66 (s, 3H), 3.73 (s, 3H), 4.06 (t, J ¼ 5.6 Hz, 2H), 4.14 (q, J ¼ 7.2 Hz, 14.4 Hz, 2H), 6.44 (s, 1H), 6.86 (s, 1H), 6.94 (s, 1H), 7.04 (s, 1H), 7.16 (d, J ¼ 7.6 Hz, 2H), 7.32e7.41 (m, 7H); 13C NMR (100 MHz, CDCl3) d 14.0, 21.1, 41.6, 55.9, 60.8, 60.9, 61.4, 109.9, 119.8, 127.1, 127.2, 127.6, 129.5, 131.1, 136.6, 137.8, 138.2, 141.0, 151.1, 151.2, 155.3, 162.3, 168.5, 169.3; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H32N2O7 567.2102; found 567.2109. 4.3.21. N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-3-phenyl-N(3,4,5-trimethoxyphenyl)propiolamide (5k) Synthesis of 5k was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.51; yielded a white solid (370 mg, 1 mmol, 74% yield). 1H NMR (500 MHz, CDCl3) d 1.35 (s, 9H), 3.65 (s, 6H), 3.81 (s, 3H), 5.60 (s, 1H), 6.03 (s, 1H), 6.46 (s, 2H), 7.10 (d, J ¼ 7.5 Hz, 2H), 7.20e7.27 (m, 7H), 7.30 (t, J ¼ 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 28.6, 51.7, 56.2, 60.9, 65.2, 82.5, 91.8, 108.6, 120.3, 128.3, 128.4, 128.6, 130.0, 130.4, 132.5, 134.3, 135.1, 138.0, 152.5, 154.9, 167.8; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H32N2O5 523.2203; found 523.2214.

4.3.22. N-(tert-butyl)-2-phenyl-2-(5,6,7-trimethoxy-2-oxo-4phenylquinolin-1(2H)-yl)acetamide (6k) Synthesis of 6k was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.58; yielded a pale yellow solid (390 mg, 1 mmol, 78% yield). 1H NMR (500 MHz, CDCl3) d 1.35 (s, 9H), 3.22 (s, 3H), 3.60 (s, 3H), 3.73 (s, 3H), 6.32 (s, 1H), 6.45 (s, 1H), 6.93 (s, 1H), 7.09 (s, 1H), 7.25e7.41 (m, 10H); 13C NMR (125 MHz, CDCl3) d 28.6, 29.6, 51.7, 55.9, 60.7, 60.8, 97.9, 109.7, 119.6, 127.1, 127.2, 127.4, 127.5, 128.4, 134.5, 136.5, 138.1, 141.1, 151.0, 151.1, 155.2, 162.4, 167.4; HRMS (ESITOF) m/z [M þ Na]þ calcd for C30H32N2O5 523.2203; found 523.2209.

2513

4.3.23. N-(2-(tert-butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)3-phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5l) Synthesis of 5l was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.50; yielded a white solid (413 mg, 1 mmol, 78% yield). 1H NMR (500 MHz, CDCl3) d 1.35 (s, 9H), 3.67 (s, 6H), 3.76 (s, 3H), 3.82 (s, 3H), 5.59 (s, 1H), 5.99 (s, 1H), 6.46 (s, 2H), 6.75 (d, J ¼ 6.8 Hz, 2H), 7.10 (t, J ¼ 5.6 Hz, 4H), 7.20 (t, J ¼ 6.0 Hz, 2H), 7.30 (t, J ¼ 6.0 Hz, 1H); 13 C NMR (125 MHz, CDCl3) d 28.6, 51.6, 55.2, 56.2, 60.9, 64.5, 82.6, 91.7, 108.6, 113.8, 120.4, 126.2, 128.3, 130.0, 131.8, 132.5, 135.1, 138.0, 152.5, 154.9, 159.7, 168.0; HRMS (ESI-TOF) m/z [M þ H]þ calcd for C31H34N2O6 531.2490; found 531.2491. 4.3.24. N-(tert-butyl)-2-(4-methoxyphenyl)-2-(5,6,7-trimethoxy2-oxo-4-phenylquinolin-1(2H)-yl)acetamide (6l) Synthesis of 6l was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.60; yielded a pale yellow solid (429 mg, 1 mmol, 81% yield). 1H NMR (500 MHz, CDCl3) d 1.34 (s, 9H), 3.21 (s, 3H), 3.66 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H), 6.22 (s, 1H), 6.44 (s, 1H), 6.85 (d, J ¼ 9.0 Hz, 2H), 6.94 (s, 1H), 6.96 (s, 1H), 7.29 (d, J ¼ 8.5 Hz, 2H), 7.34e7.41 (m, 5H); 13C NMR (125 MHz, CDCl3) d 28.6, 51.7, 55.2, 56.0, 60.7, 60.8, 109.7, 113.9, 119.8, 126.5, 127.1, 127.2, 128.9, 136.6, 138.1, 141.1, 151.0, 151.1, 155.2, 158.8, 162.4, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H34N2O6 553.2309; found 553.2321. 4.3.25. N-(1-(3-(benzyloxy)phenyl)-2-(tert-butylamino)-2oxoethyl)-3-phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5m) Synthesis of 5m was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/Hexane) 0.54; yielded a white solid (418 mg, 1 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) d 1.35 (s, 9H), 3.66 (s, 6H), 3.82 (s, 3H), 5.02 (s, 2H), 5.59 (s, 1H), 5.99 (s, 1H), 6.45 (s, 2H), 6.82 (d, J ¼ 8.4 Hz, 2H), 7.09 (t, J ¼ 6.4 Hz, 4H), 7.20 (t, J ¼ 7.6 Hz, 2H),7.29e7.34 (m, 2H), 7.37e7.40 (m, 4H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.7, 56.2, 60.9, 64.5, 82.6, 91.7, 108.6, 114.7, 120.4, 126.5, 127.4, 128.1, 128.3, 128.6, 130.0, 131.8, 132.5, 135.1, 136.5, 138.0, 152.5, 154.9, 158.9, 168.0; HRMS (ESI-TOF) m/z [M þ K]þ calcd for C37H38N2O6 645.2361; found 645.2378. 4.3.26. 2-(3-(benzyloxy)phenyl)-N-(tert-butyl)-2-(5,6,7trimethoxy-2-oxo-4-phenylquinolin-1(2H)-yl)acetamide (6m) Synthesis of 6m was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/Hexane) 0.58; yielded a pale yellow solid (455 mg, 1 mmol, 75% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 3.22 (s, 3H), 3.63 (s, 3H), 3.74 (s, 3H), 5.06 (s, 2H), 6.21 (s, 1H), 6.44 (s, 1H), 6.92 (d, J ¼ 3.6 Hz, 1H), 6.94 (s, 1H), 6.97 (s, 1H),7.28 (d, J ¼ 8.8 Hz, 2H), 7.33e7.42 (m, 10H); 13C NMR (100 MHz, CDCl3) d 28.3, 51.7, 56.0, 60.7, 60.8, 97.6, 109.7, 114.8, 119.8, 126.8, 127.1, 127.2, 127.4, 128.0, 128.5, 128.9, 136.5, 136.7, 138.1, 141.1, 151.0, 151.1, 155.2, 157.9, 162.3, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C37H38N2O6 629.2622; found 629.2631. 4.3.27. N-(2-(tert-butylamino)-1-(3-fluorophenyl)-2-oxoethyl)-3phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5n) Synthesis of 5n was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.51; yielded a white solid (337 mg, 1 mmol, 65% yield). 1H NMR (400 MHz, CDCl3) d 1.37 (s, 9H), 3.69 (s, 6H), 3.82 (s, 3H), 5.73 (s, 1H), 5.97 (s, 1H), 6.48 (s, 2H), 6.96 (t, J ¼ 8 Hz, 2H), 7.03 (d, J ¼ 8 Hz, 1H), 7.11 (d, J ¼ 7.2 Hz, 1H), 7.21 (t, J ¼ 7.6 Hz, 3H), 7.31 (t, J ¼ 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.8, 56.2, 60.9, 64.6, 82.3, 92.2, 108.3, 115.5, 115.7, 117.2, 117.5, 126.0, 126.1, 128.4, 129.9, 130.0, 130.2, 132.5, 134.9, 136.5, 136.6, 138.1, 152.7, 155.0,

2514

K. Singh et al. / Tetrahedron 75 (2019) 2506e2520

161.2, 163.7, 167.3; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H31FN2O5 541.2109; found 541.2108. 4.3.28. N-(tert-butyl)-2-(3-fluorophenyl)-2-(5,6,7-trimethoxy-2oxo-4-phenylquinolin-1(2H)-yl)acetamide (6n) Synthesis of 6n was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.67; yielded a pale yellow solid (357 mg, 1 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 3.24 (s, 3H), 3.62 (s, 3H), 3.75 (s, 3H), 6.36 (s, 1H), 6.45 (s, 1H), 6.91 (s, 1H), 6.94 (dd, J ¼ 8.4 Hz, 2.4 Hz, 1H), 7.07e7.14 (m, 3H), 7.28e7.32 (m, 1H), 7.35e7.44 (m, 5H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.8, 56.0, 60.8, 60.9, 97.7, 109.7, 114.2, 114.5, 114.6, 114.8, 119.4, 123.1, 123.2, 127.2, 127.3, 129.8, 129.9, 136.1, 136.9, 137.0, 138.3, 140.9, 151.1, 151.4, 155.4, 161.5, 162.3, 163.9, 167.0; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H31FN2O5 541.2109; found 541.2101. 4.3.29. N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-3phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5
) Synthesis of 5o was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.50; yielded a white solid (395 mg, 1 mmol, 74% yield). 1H NMR (400 MHz, CDCl3) d 1.36 (s, 9H), 3.65 (s, 6H), 3.83 (s, 3H), 5.69 (s, 1H), 5.99 (s, 1H), 6.44 (s, 1H), 6.91 (t, J ¼ 8.4 Hz, 2H), 7.10 (d, J ¼ 7.2 Hz, 2H), 7.20e7.24 (m, 4H), 7.30 (t, J ¼ 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.8, 56.2, 60.9, 64.2, 82.3, 92.2, 108.4, 120.1, 128.4, 128.6, 130.2, 131.8, 132.5, 132.7, 134.8, 138.2, 152.7, 155.0, 167.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H31ClN2O5 557.1814; found 557.1819. 4.3.30. N-(tert-butyl)-2-(4-chlorophenyl)-2-(5,6,7-trimethoxy-2oxo-4-phenylquinolin-1(2H)-yl)acetamide (6
) Synthesis of 6o was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.60; yielded a pale yellow solid (390 mg, 1 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) d 1.33 (s, 9H), 3.24 (s, 3H), 3.62 (s, 3H), 3.75 (s, 3H), 6.31 (s, 1H), 6.45 (s, 1H), 6.87 (s, 1H), 7.11 (s, 1H), 7.27e7.31 (m, 4H), 7.34e7.43 (m, 5H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.8, 56.0, 60.8, 60.9, 97.6, 109.7, 119.4, 127.3, 127.4, 128.5, 128.9, 132.8, 133.2, 136.1, 138.3, 140.9, 151.2, 151.4, 155.5, 162.3, 167.2; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H31ClN2O5 557.1814; found 557.1826. 4.3.31. N-(2-(tert-butylamino)-1-(4-cyanophenyl)-2-oxoethyl)-3phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5p) Synthesis of 5p was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (50% EtOAc/ Hexane) 0.64; yielded a white solid (409 mg, 1 mmol, 78% yield). 1H NMR (400 MHz, CDCl3) d 1.38 (s, 9H), 3.69 (s, 6H), 3.83 (s, 3H), 5.94 (s, 1H), 6.03 (s, 1H), 6.43 (s, 2H), 7.11 (d, J ¼ 7.2 Hz, 2H), 7.22 (t, J ¼ 7.2 Hz, 2H), 7.33 (t, J ¼ 7.6 Hz, 1H), 7.40 (d, J ¼ 8.4 Hz, 2H), 7.55 (d, J ¼ 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 28.5, 52.0, 56.2, 61.0, 64.5, 82.0, 92.8, 108.0, 112.4, 118.2, 119.9, 128.4, 130.4, 131.0, 132.0, 132.5, 134.5, 138.4, 139.3, 152.9, 155.1, 167.0; HRMS (ESI-TOF) m/z [M þ K]þ calcd for C31H31N3O5 564.1895; found 564.1904. 4.3.32. N-(tert-butyl)-2-(4-cyanophenyl)-2-(5,6,7-trimethoxy-2oxo-4-phenylquinolin-1(2H)-yl)acetamide (6p) Synthesis of 6p was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.60; yielded a pale yellow solid (357 mg, 1 mmol, 68% yield). 1H NMR (400 MHz, CDCl3) d 1.33 (s, 9H), 3.26 (s, 3H), 3.59 (s, 3H), 3.75 (s, 3H), 6.37 (s, 1H), 6.46 (s, 1H), 6.79 (s, 1H), 7.26 (s, 1H), 7.36e7.42 (m, 7H), 7.60 (d, J ¼ 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 28.5, 52.0, 56.0, 60.8, 60.9, 97.4, 109.7, 111.1, 118.5, 119.2,

127.4, 128.2, 131.9, 138.4, 139.5, 140.7, 151.4, 151.8, 155.7, 166.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H31N3O5 548.2156; found 548.2147. 4.3.33. N-(1-(2-bromophenyl)-2-(tert-butylamino)-2-oxoethyl)-3phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5q) Synthesis of 5q was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.51; yielded a white solid (370 mg, 1 mmol, 64% yield). 1H NMR (400 MHz, CDCl3) d 1.38 (s, 9H), 3.70 (s, 6H), 3.77 (s, 3H), 5.56 (s, 1H), 6.29 (s, 1H), 6.69 (s, 2H), 7.07e7.13 (m, 4H), 7.20e7.24 (m, 3H), 7.30 (tt, J ¼ 7.6 Hz, 1.2 Hz, 1H), 7.52e7.54 (m, 1H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.9, 56.2, 60.8, 64.1, 82.5, 91.6, 108.2, 120.3, 126.3, 127.4, 128.3, 130.0, 130.2, 131.9, 132.5, 132.7, 133.7, 134.6, 137.9, 152.4, 154.8, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H31BrN2O5 601.1309; found 601.1321. 4.3.34. 2-(2-bromophenyl)-N-(tert-butyl)-2-(5,6,7-trimethoxy-2oxo-4-phenylquinolin-1(2H)-yl)acetamide (6q) Synthesis of 6q was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.58; yielded a pale yellow solid (387 mg, 1 mmol, 67% yield). 1H NMR (400 MHz, CDCl3) d 1.33 (s, 9H), 3.22 (s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 5.57 (s, 1H), 6.42 (s, 1H), 6.45 (s, 1H), 6.66 (s, 1H), 7.23e7.25 (m, 1H), 7.33e7.39 (m, 6H), 7.58 (d, J ¼ 6.8 Hz, 1H), 7.67 (d, J ¼ 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 28.4, 51.7, 56.1, 60.8, 60.9, 64.8, 94.7, 109.7, 120.7, 124.5, 127.1, 127.2, 128.3, 130.0, 130.2, 133.3, 134.1, 138.0, 138.3, 141.1, 150.8, 151.5, 155.7, 162.0, 165.6; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H31BrN2O5 601.1309; found 601.1315. 4.3.35. N-(2-(tert-butylamino)-1-(4-fluorophenyl)-2-oxoethyl)-3phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5r) Synthesis of 5r was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.51; yielded a white solid (347 mg, 1 mmol, 67% yield). 1H NMR (400 MHz, CDCl3) d 1.36m (s, 9H), 3.68 (s, 6H), 3.82 (s, 3H), 5.69 (s, 1H), 6.02 (s, 1H), 6.43 (s, 2H), 6.91 (t, J ¼ 8.4 Hz, 2H), 7.10 (d, J ¼ 7.2 Hz, 2H), 7.20e7.24 (m, 4H), 7.30 (t, J ¼ 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.8, 56.2, 60.9, 64.1, 82.4, 92.1, 108.5, 115.2, 115.5, 120.2, 128.4, 130.1, 132.3, 132.4, 132.5, 134.8, 138.2, 152.7, 155.0, 161.5, 164.0, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H31FN2O5 541.2109; found 541.2107. 4.3.36. N-(tert-butyl)-2-(4-fluorophenyl)-2-(5,6,7-trimethoxy-2oxo-4-phenylquinolin-1(2H)-yl)acetamide (6r) Synthesis of 6r was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.58; yielded a pale yellow solid (363 mg, 1 mmol, 70% yield). 1H NMR (400 MHz, CDCl3) d 1.33 (s, 9H), 3.23 (s, 3H), 3.62 (s, 3H), 3.74 (s, 3H), 6.28 (s, 1H), 6.45 (s, 1H), 6.89 (s, 1H), 6.99 (t, J ¼ 8.4 Hz, 2H), 7.09 (s, 1H), 7.30e7.43 (m, 7H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.8, 56.0, 60.8, 60.9, 97.7, 109.7, 115.2, 115.4, 119.5, 127.2, 127.3, 129.2, 129.3, 130.1, 136.2, 138.2, 141.0, 151.1, 151.3, 155.4, 160.6, 162.4, 163.1, 167.4; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H31FN2O5 541.2109; found 541.2115. 4.3.37. N-(2-(tert-butylamino)-2-oxo-1-(3-(trifluoromethyl) phenyl)ethyl)-3-phenyl-N-(3,4,5-trimethoxyphenyl)propiolamide (5s) Synthesis of 5s was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.56; yielded a white solid (443 mg, 1 mmol, 78% yield). 1H NMR (400 MHz, CDCl3) d 1.39 (s, 9H), 3.66 (s, 6H), 3.80 (s, 3H), 5.88 (s, 1H), 6.11 (s, 1H), 6.44 (s, 2H), 7.10 (d, J ¼ 7.2 Hz, 2H), 7.21 (t,

K. Singh et al. / Tetrahedron 75 (2019) 2506e2520

J ¼ 7.6 Hz, 2H), 7.31 (t, J ¼ 7.6 Hz, 1H), 7.37 (d, J ¼ 7.6 Hz, 1H), 7.43 (d, J ¼ 8.0 Hz, 1H), 7.48 (s, 1H), 7.52 (d, J ¼ 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 28.5, 51.9, 56.1, 60.9, 82.1, 92.4, 108.3, 120.0, 125.31, 125.34, 127.61, 127.65, 128.4, 128.8, 130.2, 132.5, 133.8, 134.2, 135.0, 138.2, 152.7, 155.0, 167.3; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H31F3N2O5 591.2077; found 591.2087. 4.3.38. N-(tert-butyl)-2-(3-(trifluoromethyl)phenyl)-2-(5,6,7trimethoxy-2-oxo-4-phenylquinolin-1(2H)-yl)acetamide (6s) Synthesis of 6s was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.66; yielded a pale yellow solid (358 mg, 1 mmol, 63% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 3.24 (s, 3H), 3.60 (s, 3H), 3.74 (s, 3H), 6.40 (s, 1H), 6.47 (s, 1H), 6.88 (s, 1H), 7.21 (s, 1H), 7.35e7.45 (m, 7H), 7.53 (d, J ¼ 6.8 Hz, 1H), 7.75 (s, 1H); 13C NMR (100 MHz, CDCl3) d 28.5, 29.7, 51.9, 55.9, 60.8, 60.9, 97.6, 109.8, 119.3, 122.6, 124.23, 124.26, 124.30, 124.33, 124.50, 124.54, 124.58, 124.62, 125.3, 127.3, 127.4, 128.8, 130.5, 130.8, 135.6, 136.0, 138.4, 140.9, 151.2, 151.6, 155.6, 161.4, 167.0; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H31F3N2O5 591.2077; found 591.2087. 4.3.39. N-(2-(cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-3-(4fluorophenyl)-N-(3,4,5-trimethoxyphenyl)propiolamide (5t) Synthesis of 5t was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.51; yielded a white solid (379 mg, 1 mmol, 68% yield). 1H NMR (400 MHz, CDCl3) d 0.99e1.17 (m, 3H), 1.29e1.39 (m, 2H), 1.56e1.60 (m, 2H), 1.69 (s, 1H), 1.85 (d, J ¼ 11.2 Hz, 1H), 1.93 (d, J ¼ 9.6 Hz, 1H), 2.30 (s, 3H), 3.66 (s, 6H), 3.78e3.85 (m, 4H), 5.51 (d, J ¼ 8.0 Hz, 1H), 6.01 (s, 1H), 6.48 (s, 2H), 6.90 (t, J ¼ 8.4 Hz, 2H), 7.04e7.15 (m, 6H); 13C NMR (100 MHz, CDCl3) d 21.1, 24.7, 24.8, 25.4, 32.8, 48.8, 56.1, 60.9, 64.7, 90.6, 108.5, 115.9, 129.2, 130.2, 131.1, 134.6, 134.7, 135.2, 138.6, 152.5, 154.8, 162.2, 164.7, 167.9; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C33H35FN2O5 581.2422; found 581.2428. 4.3.40. N-cyclohexyl-2-(4-(4-fluorophenyl)-5,6,7-trimethoxy-2oxoquinolin-1(2H)-yl)-2-(p-tolyl)acetamide (6t) Synthesis of 6t was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.55; yielded a pale yellow solid (458 mg, 1 mmol, 82% yield). 1H NMR (400 MHz, CDCl3) d 1.08e1.23 (m, 3H), 1.29e1.38 (m, 2H), 1.59e1.67 (m, 3H), 1.76 (d, J ¼ 11.6 Hz, 1H), 1.98 (d, J ¼ 12.0 Hz, 1H), 2.33 (s, 3H), 3.23 (s, 3H), 3.63 (s, 3H), 3.74 (s, 3H), 3.77e3.86 (m, 1H), 6.36 (d, J ¼ 8.0 Hz, 1H), 6.41 (s, 1H), 6.99 (s, 2H), 7.06 (t, J ¼ 8.8 Hz, 2H), 7.13 (d, J ¼ 8.0 Hz, 2H), 7.25 (d, J ¼ 8.0 Hz, 2H), 7.30e7.33 (m, 2H); 13C NMR (100 MHz, CDCl3) d 21.1, 24.7, 25.5, 32.6, 32.9, 48.7, 56.0, 60.8, 61.0, 97.9, 109.7, 114.2, 114.4, 120.1, 127.4, 129.2, 129.4, 131.6, 136.6, 137.0, 137.5, 138.3, 150.0, 151.0, 155.3, 162.4, 167.3; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C33H35FN2O5 581.2422; found 581.2419. 4.3.41. N-(3,5-dimethoxyphenyl)-3-(4-fluorophenyl)-N-(2-oxo-1(p-tolyl)-2-((2,4,4-trimethylpentan-2-yl)amino)ethyl)propiolamide (5u) Synthesis of 5u was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.53; yielded a white solid (441 mg, 1 mmol, 79% yield). 1H NMR (400 MHz, CDCl3) d 0.90 (s, 9H), 1.39 (s, 3H), 1.44 (s, 3H), 1.54 (d, J ¼ 15.2 Hz, 1H), 1.71 (d, J ¼ 14.8 Hz, 1H), 2.30 (s, 3H), 3.66 (s, 6H), 5.62 (s, 1H), 5.77 (s, 1H), 6.40 (s, 1H), 6.44 (s, 2H), 6.91 (t, J ¼ 8.4 Hz, 2H), 7.05 (d, J ¼ 8.0 Hz, 2H), 7.10 (t, J ¼ 8.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.3, 28.7, 31.4, 31.5, 52.6, 55.5, 55.7, 66.4, 90.5, 101.2, 108.5, 115.6, 115.9, 116.6, 129.2, 130.1, 131.3, 134.6, 134.7, 138.4, 141.9, 154.5, 160.3, 164.6, 167.3; HRMS (ESI-TOF) m/z [M þ

2515

Na]þ calcd for C34H39FN2O4 581.2786; found 581.2789. 4.3.42. 2-(4-(4-fluorophenyl)-5,7-dimethoxy-2-oxoquinolin-1(2H)yl)-2-(p-tolyl)-N-(2,4,4-trimethylpentan-2-yl)acetamide (6u) Synthesis of 6u was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.58; yielded a pale yellow solid (446 mg, 1 mmol, 80% yield). 1H NMR (400 MHz, CDCl3) d 0.83 (s, 9H), 1.39 (s, 6H), 1.61 (d, J ¼ 2.8 Hz, 2H), 2.31 (s, 3H), 3.39 (s, 3H), 3.61 (s, 3H), 6.13 (t, J ¼ 2.4 Hz, 2H), 6.37 (s, 1H), 6.67 (d, J ¼ 2.0 Hz, 1H), 6.94 (s, 1H), 7.04 (t, J ¼ 8.0 Hz, 2H), 7.10 (d, J ¼ 8.0 Hz, 2H) 7.25e7.26 (m, 3H), 7.27 (s, 1H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.3, 28.9, 31.3, 31.5, 52.7, 53.5, 55.2, 55.6, 55.7, 94.3, 94.8, 105.7, 114.0, 114.3, 118.7, 127.7, 129.2, 131.3, 137.2, 137.9, 142.2, 150.3, 158.5, 160.9, 162.0, 162.6, 163.6, 167.2; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C34H39FN2O4 581.2786; found 581.2799. 4.3.43. (2-(N-(3,5-dimethoxyphenyl)-3-(4-fluorophenyl) propiolamido)-2-(p-tolyl)acetamido)methyl propionate (5v) Synthesis of 5v was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (55% EtOAc/ Hexane) 0.54; yielded a white solid (442 mg, 1 mmol, 83% yield). 1H NMR (500 MHz, CDCl3) d 1.24 (t, J ¼ 7.5 Hz, 3H), 2.30 (s, 3H), 3.66 (s, 6H), 4.07 (d, J ¼ 5.0 Hz, 2H), 4.16 (q, J ¼ 7.5 Hz, 14.5 Hz, 2H), 6.06 (s, 1H), 6.30 (t, J ¼ 4.5 Hz, 1H), 6.40 (s, 1H), 6.44 (s, 2H), 6.91 (t, J ¼ 8.5 Hz, 2H), 7.06 (d, J ¼ 8.0 Hz, 2H), 7.10 (t, J ¼ 7.0 Hz, 2H), 7.15 (d, J ¼ 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 14.1, 21.1, 41.7, 55.5, 61.5, 65.0, 82.3, 90.7, 101.4, 108.7, 115.7, 115.9, 116.52, 116.55, 129.3, 130.3, 130.5, 134.6, 134.7, 138.7, 141.5, 154.7, 160.3, 162.4, 164.5, 169.0, 169.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H29FN2O6 555.1902; found 555.1909. 4.3.44. (2-(4-(4-fluorophenyl)-5,7-dimethoxy-2-oxoquinolin1(2H)-yl)-2-(p-tolyl)acetamido)methyl propionate (6v) Synthesis of 6v was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (55% EtOAc/ Hexane) 0.62; yielded a pale yellow solid (367 mg, 1 mmol, 69% yield). 1H NMR (500 MHz, CDCl3) d 1.26 (t, J ¼ 7.5 Hz, 3H), 2.33 (s, 3H), 3.38 (s, 3H), 3.64 (s, 3H), 3.98 (dd, J ¼ 18.0 Hz, 5.0 Hz, 1H), 4.11e4.18 (m, 3H), 6.14 (d, J ¼ 2.0 Hz, 1H), 6.36 (s, 1H), 6.59 (d, J ¼ 2.0 Hz, 1H), 6.76 (s, 1H), 6.86 (s, 1H), 7.03 (t, J ¼ 8.5 Hz, 2H), 7.15 (d, J ¼ 8.0 Hz, 2H), 7.22 (t, J ¼ 7.0 Hz, 2H), 7.35 (d, J ¼ 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 14.0, 21.1, 41.7, 55.2, 55.4, 61.4, 93.8, 94.6, 105.8, 114.0, 114.1, 118.8, 127.7, 129.5, 131.1, 137.8, 142.2, 150.4, 158.6, 161.0, 162.0, 162.5, 163.0, 168.5, 169.3; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H29FN2O6 555.1902; found 555.1907. 4.3.45. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-N-(3,5dimethoxyphenyl)-3-(4-methoxyphenyl)propiolamide (5w) Synthesis of 5w was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/Hexane) 0.57; yielded a white solid (401 mg, 1 mmol, 78% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.29 (s, 3H), 3.65 (s, 6H), 3.77 (s, 3H), 5.68 (s, 1H), 5.88 (s, 1H), 6.39 (s, 1H), 6.43 (s, 2H), 6.73 (d, J ¼ 8.8 Hz, 2H), 7.04 (t, J ¼ 8.0 Hz, 4H), 7.11 (d, J ¼ 8.0 Hz, 2H); 13 C NMR (125 MHz, CDCl3) d 21.2, 28.7, 51.7, 55.3, 55.5, 65.6, 82.0, 92.4, 101.3, 108.7, 112.4, 114.0, 129.2, 130.1, 131.4, 134.4, 138.4, 141.8, 155.1, 160.3, 161.0, 168.1; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H34N2O5 537.2360; found 537.2368. 4.3.46. N-(tert-butyl)-2-(5,7-dimethoxy-4-(4-methoxyphenyl)-2oxoquinolin-1(2H)-yl)-2-(p-tolyl)acetamide (6w) Synthesis of 6w was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/Hexane) 0.63; yielded a pale yellow solid (375 mg, 1 mmol,

2516

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73% yield). 1H NMR (400 MHz, CDCl3) d 1.32 (s, 9H), 2.31 (s, 3H), 3.42 (s, 3H), 3.61 (s, 3H), 3.87 (s, 3H), 6.15 (d, J ¼ 2.4 Hz, 2H), 6.39 (s, 1H), 6.67 (d, J ¼ 2.4 Hz, 1H), 6.89 (d, J ¼ 8.4 Hz, 2H), 6.93 (s, 1H), 7.10 (d, J ¼ 8.4 Hz, 2H), 7.22e7.26 (m, 4H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.6, 51.6, 55.3, 55.6, 94.3, 94.9, 106.0, 112.6, 118.7, 127.6, 128.6, 129.2, 131.5, 134.4, 137.2, 142.3, 151.1, 158.7, 158.9, 161.8, 162.8, 167.8; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H34N2O5 537.2360; found 537.2351. 4.3.47. 3-(4-methoxyphenyl)-N-(2-oxo-1-(p-tolyl)-2-((2,4,4trimethylpentan-2-yl)amino)ethyl)-N-(3,4,5 -trimethoxyphenyl) propiolamide (5x) Synthesis of 5x was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.57; yielded a white solid (510 mg, 1 mmol, 85% yield). 1H NMR (400 MHz, CDCl3) d 0.91 (s, 9H), 1.39 (s, 3H), 1.43 (s, 3H), 1.56 (d, J ¼ 14.8 Hz, 1H), 1.71 (d, J ¼ 14.8 Hz, 1H), 2.29 (s, 3H), 3.66 (s, 6H), 3.76 (s, 3H), 3.83 (s, 3H), 5.63 (s, 1H), 5.90 (s, 1H), 6.46 (s, 2H), 6.72 (d, J ¼ 8.8 Hz, 2H), 7.03 (d, J ¼ 8.8 Hz, 4H), 7.09 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.5, 28.8, 31.4, 31.5, 52.7, 55.3, 55.7, 56.2, 61.0, 65.7, 82.1, 92.5, 108.5, 112.3, 114.1, 129.2, 130.4, 131.5, 134.3, 135.8, 138.0, 138.5, 152.6, 155.2, 161.0, 167.6; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C36H44N2O6 623.3092; found 623.3084. 4.3.48. 2-(p-tolyl)-2-(5,6,7-trimethoxy-4-(4-methoxyphenyl)-2oxoquinolin-1(2H)-yl)-N-(2,4,4-trimethylpentan-2-yl)acetamide (6x) Synthesis of 6x was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.62; yielded a pale yellow solid (468 mg, 1 mmol, 78% yield). 1H NMR (400 MHz, CDCl3) d 0.81 (s, 9H), 1.40 (s, 6H), 1.60 (d, J ¼ 11.2 Hz, 2H), 2.32 (s, 3H), 3.23 (s, 3H), 3.63 (s, 3H), 3.75 (s, 3H), 3.87 (s, 3H), 6.18 (s, 1H), 6.44 (s, 1H), 6.91 (d, J ¼ 4.4 Hz, 2H), 6.94 (s, 1H), 7.07 (s, 1H), 7.11 (d, J ¼ 8.4 Hz, 2H), 7.25e7.29 (m, 4H); 13C NMR (100 MHz, CDCl3) d 21.2, 28.3, 29.0, 31.2, 31.5, 52.6, 55.3, 55.7, 56.0, 61.0, 97.9, 109.8, 112.7, 119.9, 127.6, 128.9, 129.1, 131.3, 133.4, 136.7, 137.1, 138.3, 150.8, 151.3, 155.2, 159.0, 162.4, 167.2; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C36H44N2O6 623.3092; found 623.3084. 4.3.49. (2-(3-(4-methoxyphenyl)-N-(3,4,5-trimethoxyphenyl) propiolamido)-2-(p-tolyl)acetamido)methyl propionate (5y) Synthesis of 5y was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (50% EtOAc/ Hexane) 0.60; yielded a white solid (465 mg, 1 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) d 1.24 (t, J ¼ 7.2 Hz, 3H), 2.29 (s, 3H), 3.66 (s, 6H), 3.76 (s, 3H), 3.83 (s, 3H), 4.07 (d, J ¼ 5.2 Hz, 2H), 4.15 (q, J ¼ 7.2 Hz, 14.4 Hz, 2H), 6.17 (s, 1H), 6.35 (t, J ¼ 5.2 Hz, 1H), 6.47 (s, 1H), 6.72 (d, J ¼ 8.8 Hz, 2H), 7.03e7.07 (m, 4H), 7.12 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 14.1, 15.3, 21.1, 41.7, 55.3, 56.2, 61.0, 61.5, 64.4, 65.9, 82.0, 92.8, 108.7, 112.2, 114.1, 129.2, 130.5, 130.7, 134.4, 135.3, 138.1, 138.8, 152.6, 155.4, 161.1, 169.3, 169.6; HRMS (ESITOF) m/z [M þ Na]þ calcd for C32H34N2O8 597.2207; found 597.2219. 4.3.50. (2-(p-tolyl)-2-(5,6,7-trimethoxy-4-(4-methoxyphenyl)-2oxoquinolin-1(2H)-yl)acetamido)methyl propionate (6y) Synthesis of 6y was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (50% EtOAc/ Hexane) 0.70; yielded a pale yellow solid (385 mg, 1 mmol, 67% yield). 1H NMR (500 MHz, CDCl3) d 1.20 (t, J ¼ 6.5 Hz, 3H), 2.33 (s, 3H), 3.22 (s, 3H), 3.65 (s, 3H), 3.75 (s, 3H), 3.86 (s, 3H), 4.05e4.08 (m, 2H), 4.14 (q, J ¼ 7.0 Hz, 14.5 Hz, 2H), 6.43 (s, 1H), 6.86 (s, 1H), 6.90 (s, 1H), 6.91 (d, J ¼ 8.0 Hz, 2H), 7.05 (s, 1H), 7.15 (d, J ¼ 7.5 Hz, 2H), 7.27 (d, J ¼ 8.0 Hz, 2H), 7.33 (d, J ¼ 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 14.0, 21.0, 41.6, 55.3, 55.9, 60.9, 61.4, 97.3, 109.9,

112.7, 120.0, 127.5, 128.8, 129.4, 131.2, 133.3, 136.6, 137.6, 138.3, 150.8, 151.3, 155.2, 158.9, 162.4, 168.6, 169.2; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H34N2O8 597.2207; found 597.2218. 4.3.51. N-(2-(cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-3-(p-tolyl)N-(3,4,5-trimethoxyphenyl)propiolamide (5z) Synthesis of 5z was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.59; yielded a white solid (393 mg, 1 mmol, 71% yield). 1H NMR (400 MHz, CDCl3) d 1.01e1.14 (m, 3H), 1.31e1.40 (m, 2H), 1.56e1.61 (m, 3H), 1.86 (d, J ¼ 9.2 Hz, 1H), 1.93 (d, J ¼ 9.2 Hz, 1H), 2.29 (s, 6H), 3.66 (s, 6H), 3.82 (s, 3H), 3.84e3.86 (m, 1H), 5.58 (d, J ¼ 8.0 Hz, 1H), 6.02 (s, 1H), 6.48 (s, 1H), 7.0e7.05 (m, 6H), 7.09 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.1, 21.6, 24.7, 24.8, 25.5, 32.8, 3.9, 48.8, 56.2, 60.9, 64.8, 92.3, 108.7, 117.3, 129.2, 129.3, 130.3, 131.3, 132.5, 135.5, 138.6, 140.6, 152.5, 168.1; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C34H38N2O5 577.2673; found 577.2677. 4.3.52. N-cyclohexyl-2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4-(ptolyl)quinolin-1(2H)-yl)acetamide (6z) Synthesis of 6z was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.63; yielded a pale yellow solid (360 mg, 1 mmol, 65% yield). 1H NMR (400 MHz, CDCl3) d 1.07e1.22 (m, 3H), 1.28e1.40 (m, 2H), 1.54e1.62 (m, 3H), 1.75 (dd, J ¼ 4.0 Hz, 12.4 Hz, 1H), 1.97 (dd, J ¼ 3.6 Hz, 12.4 Hz, 1H), 2.32 (s, 3H), 2.41 (s, 3H), 3.22 (s, 3H), 3.62 (s, 3H), 3.73 (s, 3H), 3.77e3.86 (m, 1H), 6.42 (s, 2H), 6.99 (s, 1H), 7.01 (s, 1H), 7.12 (d, J ¼ 8.0 Hz, 2H), 7.18e7.25 (m, 5H), 7.27 (s, 1H); 13C NMR (100 MHz, CDCl3) d 21.1, 21.3, 24.6, 24.7, 25.5, 32.6, 32.9, 48.6, 56.0, 60.97, 60.99, 110.0, 119.8, 127.4, 128.0, 129.3, 131.6, 136.9, 137.3, 138.2, 138.3, 151.2, 155.2, 162.6, 167.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C34H38N2O5 577.2673; found 577.2681. 4.3.53. N-(2-oxo-1-(p-tolyl)-2-((2,4,4-trimethylpentan-2-yl) amino)ethyl)-3-(p-tolyl)-N-(3,4,5-trimethoxyphenyl)propiolamide (5a0 ) Synthesis of 5a0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.56; yielded a white solid (415 mg, 1 mmol, 71% yield). 1H NMR (500 MHz, CDCl3) d 0.91 (s, 9H), 1.39 (s, 3H), 1.44 (s, 3H), 1.56 (d, J ¼ 14.5 Hz, 1H), 1.72 (d, J ¼ 15.0 Hz, 1H), 2.29 (s, 6H), 3.66 (s, 6H), 3.82 (s, 3H), 5.61 (s, 1H), 5.90 (s, 1H), 6.47 (s, 2H), 6.99e7.10 (m, 8H); 13 C NMR (125 MHz, CDCl3) d 21.0, 21.5, 28.4, 28.8, 31.4, 31.5, 52.7, 55.7, 56.2, 60.9, 65.7, 82.3, 92.2, 108.5, 117.3, 129.1, 130.3, 131.4, 132.4, 135.7, 138.0, 138.4, 140.5, 152.6, 155.0, 167.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C36H44N2O5 607.3142; found 607.3154. 4.3.54. 2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4-(p-tolyl)quinolin1(2H)-yl)-N-(2,4,4-trimethylpentan-2-yl)acetamide (6a0 ) Synthesis of 6a0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.73; yielded a pale yellow solid (432 mg, 1 mmol, 74% yield). 1H NMR (400 MHz, CDCl3) d 0.81 (s, 9H), 1.40 (s, 6H), 1.60 (d, J ¼ 10.4 Hz, 2H), 2.32 (s, 3H), 2.42 (s, 3H), 3.22 (s, 3H), 3.63 (s, 3H), 3.74 (s, 3H), 6.19 (s, 1H), 6.44 (s, 1H), 6.90 (s, 1H), 7.08 (s, 1H), 7.11 (d, J ¼ 8.0 Hz, 2H), 7.21 (d, J ¼ 4.0 Hz, 4H), 7.25 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.1, 21.3, 28.3, 29.0, 31.2, 31.5, 52.6, 55.7, 56.0, 61.0, 97.8, 109.8, 119.8, 127.4, 127.6, 128.0, 129.1, 131.3, 136.7, 136.9, 137.1, 138.2, 138.3, 151.2, 151.3, 155.3, 162.4, 167.2; HRMS (ESITOF) m/z [M þ Na]þ calcd for C36H44N2O5 607.3142; found 607.3153. 4.3.55. (2-(p-tolyl)-2-(3-(p-tolyl)-N-(3,4,5-trimethoxyphenyl) propiolamido)acetamido)methyl propionate (5b0 ) Synthesis of 5b0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (50%

K. Singh et al. / Tetrahedron 75 (2019) 2506e2520

EtOAc/Hexane) 0.64; yielded a white solid (407 mg, 1 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) d 1.24 (t, J ¼ 7.2 Hz, 3H), 2.29 (s, 6H), 3.65 (s, 6H), 3.82 (s, 3H), 4.06 (d, J ¼ 5.2 Hz, 2H), 4.15 (q, J1 ¼ 7.2 Hz, J2 ¼ 14.4 Hz, 2H), 6.17 (s, 1H), 6.34 (s, 1H), 6.46 (s, 1H), 6.98e7.07 (m, 6H), 7.12 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 14.1, 21.1, 21.6, 41.7, 56.2, 60.9, 61.5, 64.4, 82.2, 92.5, 108.6, 117.2, 129.2, 129.3, 130.6, 132.6, 135.2, 138.1, 138.8, 140.7, 152.6, 155.3, 169.3, 169.6; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H34N2O7 581.2258; found 581.2253. 4.3.56. (2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4-(p-tolyl)quinolin1(2H)-yl)acetamido)methyl propionate (6b0 ) Synthesis of 6b0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (50% EtOAc/Hexane) 0.75; yielded a pale yellow solid (363 mg, 1 mmol, 65% yield). 1H NMR (400 MHz, CDCl3) d 1.20 (t, J ¼ 7.2 Hz, 3H), 2.33 (s, 3H), 2.41 (s, 3H), 3.21 (s, 3H), 3.65 (s, 3H), 3.23 (s, 3H), 4.05e4.09 (m, 2H), 4.13 (q, J1 ¼ 7.2 Hz, J2 ¼ 14.0 Hz, 2H), 6.43 (s, 1H), 6.85 (s, 1H), 6.89 (t, J ¼ 5.6 Hz, 1H), 7.05 (s, 1H), 7.15 (d, J ¼ 8.4 Hz, 2H), 7.18 (q, J1 ¼ 8.0 Hz, J2 ¼ 14.4 Hz, 4H), 7.33 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 14.1, 21.1, 21.3, 41.7, 56.0, 60.9, 61.5, 97.2, 110.1, 120.0, 127.3, 127.6, 128.0, 129.5, 131.2, 136.7, 136.9, 137.7, 138.2, 138.4, 151.3, 151.4, 155.3, 162.5, 168.7, 169.3; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C32H34N2O7 581.2258; found 581.2247. 4.3.57. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-N-(3,5dimethoxyphenyl)-3-(p-tolyl)propiolamide (5c0 ) Synthesis of 5c0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.66; yielded a white solid (329 mg, 1 mmol, 66% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.29e2.30 (m, 6H), 3.65 (s, 6H), 5.56 (s, 1H), 5.87 (s, 1H), 6.38 (s, 1H), 6.43 (s, 2H), 7.03e7.06 (m, 5H), 7.11 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.2, 21.6, 28.7, 51.7, 55.5, 92.2, 101.3, 108.8, 117.4, 129.1, 129.2, 130.1, 130.2, 131.4, 132.5, 138.4, 160.3, 168.1; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H34N2O4 521.2411; found 521.2422.

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4.3.60. N-(tert-butyl)-2-(5,7-dimethoxy-2-oxo-4-phenylquinolin1(2H)-yl)-2-phenylacetamide (6d0 ) Synthesis of 6d0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/Hexane) 0.53; yielded a pale yellow solid (371 mg, 1 mmol, 79% yield). 1H NMR (400 MHz, CDCl3) d 1.33 (s, 9H), 3.36 (s, 3H), 3.58 (s, 3H), 6.14 (d, J ¼ 2.0 Hz, 1H), 6.19 (s, 1H), 6.41 (s, 1H), 6.67 (d, J ¼ 2.4 Hz, 1H), 7.04 (s, 1H), 7.24e7.32 (m, 4H), 7.33e7.39 (m, 6H); 13 C NMR (100 MHz, CDCl3) d 28.5, 51.6, 52.2, 55.5, 94.3, 94.9, 105.8, 118.4, 127.0, 127.1, 127.4, 127.5, 128.4, 134.4, 141.8, 142.0, 151.5, 158.5, 161.8, 162.7, 167.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C29H30N2O4 493.2098; found 493.2091. 4.3.61. N-(2-(tert-butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)N-(3,5-dimethoxyphenyl)-3-phenylpropiolamide (5e0 ) Synthesis of 5e0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.60; yielded a white solid (365 mg, 1 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) d 1.35 (s, 9H), 3.66 (s, 6H), 3.76 (s, 3H), 5.66 (s, 1H), 5.90 (s, 1H), 6.39e6.43 (m, 3H), 6.75 (d, J ¼ 8.4 Hz, 2H), 7.12 (t, J ¼ 8.8 Hz, 4H), 7.21 (t, J ¼ 7.6 Hz, 2H), 7.30 (t, J ¼ 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.6, 55.2, 55.5, 65.0, 82.5, 91.6, 101.2, 108.7, 113.8, 120.4, 126.2, 128.3, 129.9, 131.6, 132.5, 141.3, 154.7, 159.6, 160.2, 168.0; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H32N2O5 523.2203; found 523.2214. 4.3.62. N-(tert-butyl)-2-(5,7-dimethoxy-2-oxo-4-phenylquinolin1(2H)-yl)-2-(4-methoxyphenyl)acetamide (6e0 ) Synthesis of 6e0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.53; yielded a pale yellow solid (385 mg, 1 mmol, 77% yield). 1H NMR (400 MHz, CDCl3) d 1.32 (s, 9H), 3.36 (s, 3H), 3.63 (s, 3H), 3.78 (s, 3H), 6.09 (s, 1H), 6.14 (d, J ¼ 2.4 Hz, 1H), 6.40 (s, 1H), 6.67 (d, J ¼ 2.0 Hz, 1H), 6.84 (d, J ¼ 8.8 Hz, 2H), 6.91 (s, 1H), 7.28e7.38 (m, 7H); 13C NMR (100 MHz, CDCl3) d 28.5, 51.6, 55.22, 55.24, 55.5, 94.1, 94.7, 105.8, 113.8, 118.5, 126.4, 127.0, 127.1, 129.0, 141.9, 142.1, 151.3, 158.5, 158.7, 161.8, 162.6, 167.8; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H32N2O5 523.2203; found 523.2213.

4.3.58. N-(tert-butyl)-2-(5,7-dimethoxy-2-oxo-4-(p-tolyl)quinolin1(2H)-yl)-2-(p-tolyl)acetamide (6c0 ) Synthesis of 6c0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.72; yielded a pale yellow solid (378 mg, 1 mmol, 76% yield). 1H NMR (400 MHz, CDCl3) d 1.32 (s, 9H), 2.31 (s, 3H), 2.40 (s, 3H), 3.38 (s, 3H), 3.61 (s, 3H), 6.14 (d, J ¼ 2.4 Hz, 1H), 6.16 (s, 1H), 6.39 (s, 1H), 6.68 (d, J ¼ 2.4 Hz, 1H), 6.94 (s, 1H), 7.10 (d, J ¼ 8.0 Hz, 2H), 7.17 (d, J ¼ 2.0 Hz, 4H), 7.24e7.26 (m, 2H); 13C NMR (100 MHz, CDCl3) d 21.1, 21.3, 28.6, 51.6, 55.3, 55.5, 94.3, 94.9, 95.0, 106.0, 118.7, 127.6, 127.9, 129.1, 131.6, 136.7, 137.2, 139.0, 142.2, 151.5, 158.7, 161.8, 162.8, 167.8; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C31H34N2O4 521.2411; found 521.2418.

4.3.63. N-(2-(tert-butylamino)-1-(4-fluorophenyl)-2-oxoethyl)-N(3,5-dimethoxyphenyl)-3-phenylpropiolamide (5f0 ) Synthesis of 5f0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.56; yielded a white solid (327 mg, 1 mmol, 67% yield). 1H NMR (400 MHz, CDCl3) d 1.36 (s, 9H), 3.67 (s, 6H), 5.77 (s, 1H), 5.94 (s, 1H), 6.40 (d, J ¼ 1.6 Hz, 3H), 6.91 (t, J ¼ 8.4 Hz, 2H), 7.12 (d, J ¼ 7.2 Hz, 2H), 7.22e7.25 (m, 4H), 7.31 (t, J ¼ 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.7, 55.5, 64.5, 82.3, 92.0, 101.2, 108.7, 115.2, 115.4, 120.2, 128.3, 129.9, 130.0, 130.1, 132.1, 132.2, 132.5, 140.9, 154.8, 160.3, 161.4, 163.9, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C29H29FN2O4 511.2004; found 511.1993.

4.3.59. N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-N-(3,5dimethoxyphenyl)-3-phenylpropiolamide (5d0 ) Synthesis of 5d0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/Hexane) 0.56; yielded a white solid (310 mg, 1 mmol, 66% yield). 1H NMR (400 MHz, CDCl3) d 1.35 (s, 9H), 3.66 (s, 6H), 5.67 (s, 1H), 5.93 (s, 1H), 6.37 (t, J ¼ 2.0 Hz, 1H), 6.42 (s, 2H), 7.12 (d, J ¼ 7.6 Hz, 2H), 7.21e7.25 (m, 7H), 7.30 (t, J ¼ 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.7, 55.5, 65.7, 82.4, 91.7, 101.2, 108.7, 120.4, 128.3, 128.4, 128.6, 129.9, 130.2, 132.5, 134.2, 141.3, 154.8, 160.2, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C29H30N2O4 493.2098; found 493.2106.

4.3.64. N-(tert-butyl)-2-(5,7-dimethoxy-2-oxo-4-phenylquinolin1(2H)-yl)-2-(4-fluorophenyl)acetamide (6f0 ) Synthesis of 6f0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.56; yielded a pale yellow solid (351 mg, 1 mmol, 72% yield). 1H NMR (400 MHz, CDCl3) d 1.31 (s, 9H), 3.37 (s, 3H), 3.60 (s, 3H), 6.16 (d, J ¼ 2 Hz, 2H), 6.41 (s, 1H), 6.63 (d, J ¼ 2 Hz, 1H), 6.98 (t, J ¼ 8.8 Hz, 2H), 7.02 (s, 1H), 7.29e7.38 (m, 7H); 13C NMR (100 MHz, CDCl3) d 28.5, 51.7, 55.2, 55.5, 94.2, 95.0, 105.7, 115.1, 115.3, 118.2, 127.1, 127.2, 129.3, 129.4, 129.9, 130.0, 134.0, 134.2, 141.7, 151.7, 158.6, 160.6, 162.0, 162.6, 163.1, 167.5; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C29H29FN2O4 511.2004; found 511.2015.

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4.3.65. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-N-(3,5dimethoxyphenyl)-3-phenylpropiolamide (5g0 ) Synthesis of 5g0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.56; yielded a white solid (363 mg, 1 mmol, 75% yield). 1H NMR (400 MHz, CDCl3) d 1.34 (s, 9H), 2.30 (s, 3H), 3.65 (s, 6H), 5.63 (s, 1H), 5.88 (s, 1H), 6.38 (s, 1H), 6.44 (s, 2H), 7.04 (d, J ¼ 8 Hz, 2H), 7.11e7.14 (m, 4H), 7.21 (t, J ¼ 7.6 Hz, 2H), 7.30 (t, J ¼ 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.6, 51.6, 55.5, 65.6, 82.5, 91.6, 101.2, 108.6, 120.4, 128.3, 129.1, 129.9, 130.1, 131.2, 132.5, 138.4, 141.5, 154.7, 160.2, 167.9; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H32N2O4 507.2254; found 507.2262. 4.3.66. N-(tert-butyl)-2-(5,7-dimethoxy-2-oxo-4-phenylquinolin1(2H)-yl)-2-(p-tolyl)acetamide (6g0 ) Synthesis of 6g0 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.66; yielded a pale yellow solid (392 mg, 1 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) d 1.32 (s, 9H), 2.31 (s, 3H), 3.36 (s, 3H), 3.61 (s, 3H), 6.14 (d, J ¼ 2.0 Hz, 2H), 6.40 (s, 1H), 6.67 (d, J ¼ 2.4 Hz, 1H), 6.93 (s, 1H), 7.11 (d, J ¼ 8.0 Hz, 2H), 7.25e7.30 (m, 4H), 7.33e7.38 (m, 3H); 13C NMR (100 MHz, CDCl3) d 21.0, 28.5, 51.6, 55.2, 55.5, 94.2, 94.7, 105.8, 118.5, 127.0, 127.1, 127.5, 129.1, 131.4, 137.2, 141.9, 142.1, 151.3, 158.5, 161.8, 162.7, 167.7; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C30H32N2O4 507.2254; found 507.2263. 4.4. Procedure for the synthesis of compound 2-(p-tolyl)-2-(5,6,7trimethoxy-2-oxo-4-phenylquinolin-1(2H)-yl)acetamide 7 In a dry glass voil, equipped with magnetic stirrer, added the compound 6a (103 mg, 0.2 mmol) along with TFA (3e4 mL), anisole (3e4 mL) and conc.H2SO4 (39.2 mg, 0.4 mmol). The reaction mixture was refluxed for 24 h and then cooled it to room temperature. The mixture of ice cold water and n-hexane 40 mL (50:50) was poured into the reaction mixture. The precipitate came out, filtered and dried, then subjected to the purification to afford the compound 7 as a light brown solid. 4.4.1. 2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-4-phenylquinolin1(2H)-yl)acetamide (7) Synthesis of 7 was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.58; yielded a light brown solid (256 mg, 1 mmol, 56% yield). 1H NMR (400 MHz, CDCl3) d 2.10 (s, 3H), 3.58 (s, 3H), 3.68 (s, 3H), 3.77 (s, 1H), 4.67 (s, 1H), 6.29 (s, 1H), 6.51 (s, 1H), 6.70 (s, 1H), 6.83 (d, J ¼ 7.2 Hz, 2H), 7.08 (s, 2H), 7.19e7.23 (m, 5H); 13C NMR (100 MHz, CDCl3) d 20.9, 29.7, 55.8, 60.6, 60.7, 109.9, 120.0, 126.8, 127.0, 128.0, 128.9, 134.0, 136.4, 137.3, 138.1, 141.2, 150.6, 150.9, 155.3, 162.6, 173.9; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C27H26N2O5 481.1734; found 481.1748.

4.5.1. N-cyclohexyl-2-(p-tolyl)-2-(5,6,7-trimethoxy-2-oxo-3,4diphenylquinolin-1(2H)-yl)acetamide (9a) Synthesis of 9a was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (40% EtOAc/ Hexane) 0.59; yielded a white solid (329 mg, 1 mmol, 61% yield). 1H NMR (400 MHz, CDCl3) d 1.10e1.21 (m, 3H), 1.28e1.40 (m, 2H), 1.57 (s, 1H), 1.64e1.70 (m, 2H), 1.80 (d, J ¼ 10.8 Hz, 1H), 1.96 (d, J ¼ 9.6 Hz, 1H), 2.33 (s, 3H), 3.13 (s, 3H), 3.62 (s, 3H), 3.71 (s, 3H), 3.79e3.87 (m, 1H), 6.55 (d, J ¼ 8 Hz, 1H), 7.01e7.16 (m, 14H), 7.28 (d, J ¼ 8 Hz, 2H); 13 C NMR (100 MHz, CDCl3) d 21.0, 24.6, 24.7, 25.4, 32.5, 32.8, 48.6, 55.9, 60.7, 110.3, 126.0, 126.5, 126.7, 127.2, 127.3, 128.3, 128.4, 129.2, 130.7, 131.7, 136.0, 137.1, 138.3, 139.8, 147.5, 151.4, 154.7, 162.7, 167.4; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C39H40N2O5 639.2829; found 639.2839. 4.5.2. N-(tert-butyl)-2-(4-cyanophenyl)-2-(5,6,7-trimethoxy-2oxo-3,4-diphenylquinolin-1(2H)-yl)acetamide (9b) Synthesis of 9b was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (45% EtOAc/ Hexane) 0.66; yielded a white solid (445 mg, 1 mmol, 74% yield). 1H NMR (400 MHz, CDCl3) d 1.35 (s, 9H), 3.18 (s, 3H), 3.61 (s, 3H), 3.73 (s, 3H), 6.86 (s, 1H), 6.99 (d, J ¼ 6.8 Hz, 2H), 7.10e7.18 (m, 8H), 7.37e7.43 (m, 2H), 7.44 (d, J ¼ 8.0 Hz, 2H), 7.62 (d, J ¼ 8.4 Hz, 2H); 13 C NMR (100 MHz, CDCl3) d 28.6, 52.0, 56.0, 60.7, 65.8, 110.2, 111.1, 126.3, 126.7, 126.8, 126.9, 127.4, 128.1, 128.2, 128.3, 130.5, 132.0, 135.5, 138.7, 139.4, 139.8, 148.2, 151.8, 155.3, 162.6, 166.9; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C37H35N3O5 624.2469; found 624.2461. 4.6. General procedure for the synthesis of N-(tert-butyl)-2-phenyl2-((3,4,5-trimethoxyphenyl)amino)acetamide (6aa6ac) using Pd (II) catalyst To a dry screw capped glass vial, backfilled with nitrogen, added the Ugi products (5aa¡5ac) along with DCE. The catalyst Pd(CH3CN)4(BF4)2 (10 mol %) was added and stirred at 50
C in oil bath for 12 h. After completion the reaction, the reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). Collect the Organic layer, dried over sodium sulphate and evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (10e20% EtOAc in hexane) to afford pure compounds.

4.5. Suzuki-Miyaura coupling of 8: synthesis of 5,6,7-trimethoxy3,4-diphenylquinolin-2(1H)-one scaffolds (9a-9b)

4.6.1. N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-N,3diphenylpropiolamide (5aa) Synthesis of 5aa was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (30% EtOAc/Hexane) 0.57; yielded a white solid (312 mg, 1 mmol, 76% yield). 1H NMR (400 MHz, CDCl3) d 1.36 (s, 9H), 5.68 (s, 1H), 6.00 (s, 1H), 7.02 (d, J ¼ 7.2 Hz, 2H), 7.17e7.24 (m, 10H), 7.27e7.31 (m, 1H); 13 C NMR (100 MHz, CDCl3) d 28.6, 51.7, 65.4, 82.5, 92.1, 120.3, 128.2, 128.3, 128.4, 128.5, 129.9, 130.2, 130.9, 132.5, 134.1, 139.7, 155.0, 168.0; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C27H26N2O2 433.1886; found 433.1893.

To a solution of (8a-8b) (1 eq, 0.02 mmol) in dry toluene (1.0 mL) and aq. K2CO3 (2 M, 1 mL) was added phenylboronic acid (2 eq, 0.04 mmol) and Pd(PPh3)4 as catalyst (0.1 eq, 0.002 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at 80
C for 12 h. After completion, reaction was cooled to room temperature, diluted with ethylacetate (5 mL), and extracted the organic layer (3  10 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SO4 and evaporated under afforded coupling vacuo. The residue obtained was purified by silica gel flash column chromatography to produce compound (9a-9b).

4.6.2. N-(tert-butyl)-2-phenyl-2-(phenylamino)acetamide (6aa) Synthesis of 6aa was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (30% EtOAc/Hexane) 0.60; yielded a pale yellow solid (178 mg, 1 mmol, 63% yield). 1H NMR (400 MHz, CDCl3) d 1.31 (s, 9H), 4.48 (s, 1H), 4.59 (d, J ¼ 1.6 Hz, 1H), 6.55 (s, 1H), 6.62 (dd, J ¼ 8.4 Hz, 0.8 Hz, 2H), 6.78 (tt, J ¼ 7.2 Hz, 1.2 Hz, 1H), 7.17 (t, J ¼ 7.8 Hz, 2H), 7.31e7.43 (m, 5H); 13 C NMR (100 MHz, CDCl3) d 28.5, 51.1, 64.9, 113.8, 119.0, 127.3, 128.4, 129.2, 129.3, 139.2, 146.7, 170.2; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C18H22N2O 305.1624; found 305.1617.

K. Singh et al. / Tetrahedron 75 (2019) 2506e2520

4.6.3. N-(2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-N,3diphenylpropiolamide (5 ab) Synthesis of 5 ab was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (30% EtOAc/Hexane) 0.62; yielded a white solid (352 mg, 1 mmol, 83% yield). 1H NMR (400 MHz, CDCl3) d 1.35 (s, 9H), 2.27 (s, 3H), 5.66 (s, 1H), 5.96 (s, 1H), 7.00 (t, J ¼ 8 Hz, 4H), 7.07 (d, J ¼ 8.4 Hz, 2H), 7.17 (t, J ¼ 7.2 Hz, 2H), 7.24e7.30 (m, 6H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.6, 51.7, 65.2, 82.5, 92.0, 120.3, 128.2, 128.3, 129.1, 129.9, 130.1, 130.9, 131.1, 132.5, 138.3, 139.9, 155.0, 168.1; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C28H28N2O2 447.2043; found 447.2060. 4.6.4. N-(tert-butyl)-2-(phenylamino)-2-(p-tolyl)acetamide (6 ab) Synthesis of 6 ab was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (30% EtOAc/Hexane) 0.65; yielded a pale yellow solid (142 mg, 1 mmol, 48% yield). 1H NMR (400 MHz, CDCl3) d 1.31 (s, 9H), 2.34 (s, 3H), 4.46 (s, 1H), 4.55 (s, 1H), 6.50 (s, 1H), 6.60 (d, J ¼ 8.0 Hz, 2H), 6.77 (t, J ¼ 7.2 Hz, 1H), 7.15e7.19 (m, 4H), 7.29 (d, J ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 21.1, 28.5, 51.1, 64.6, 113.8, 118.9, 127.2, 129.2, 129.8, 136.3, 138.2, 146.9, 170.4; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C19H24N2O 319.1781; found 319.1784. 4.6.5. N-(2-(tert-butylamino)-2-oxo-1-(3-(trifluoromethyl)phenyl) ethyl)-N,3-diphenylpropiolamide (5ac) Synthesis of 5ac was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (20% EtOAc/Hexane) 0.53; yielded a white solid (378 mg, 1 mmol, 79% yield). 1H NMR (400 MHz, CDCl3) d 1.39 (s, 9H), 5.94 (s, 1H), 6.10 (s, 1H), 7.02 (d, J ¼ 7.6 Hz, 2H), 7.18e7.35 (m, 9H), 7.41 (d, J ¼ 8.0 Hz, 1H), 7.45 (s, 1H), 7.48 (d, J ¼ 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 28.6, 51.9, 64.2, 82.2, 92.8, 120.0, 125.2, 125.3, 127.41, 127.44, 128.3, 128.6, 128.7, 130.1, 130.8, 132.5, 133.7, 134.9, 139.0, 155.1, 167.4; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C28H25F3N2O2 501.1760; found 501.1749. 4.6.6. N-(tert-butyl)-2-(phenylamino)-2-(3-(trifluoromethyl) phenyl)acetamide (6ac) Synthesis of 6ac was achieved according to the general procedure and purified by flash column chromatography Rf ¼ (20% EtOAc/Hexane) 0.58; yielded a pale yellow solid (185 mg, 1 mmol, 53% yield). 1H NMR (400 MHz, CDCl3) d 1.32 (s, 9H), 4.47 (s, 1H), 4.67 (s, 1H), 6.56 (s, 1H), 6.62 (dd, J ¼ 8.6 Hz, 0.8 Hz, 2H), 6.81 (t, J ¼ 7.2 Hz, 1H), 7.18 (t, J ¼ 7.8 Hz, 2H), 7.48 (t, J ¼ 7.6 Hz, 1H), 7.59 (t, J ¼ 8.4 Hz, 2H), 7.68 (s, 1H); 13C NMR (100 MHz, CDCl3) d 28.9, 51.4, 64.4, 113.9, 119.5, 122.4, 124.03, 124.07, 124.11, 124.15, 125.20, 125.33, 125.37, 125.40, 125.44, 129.3, 129.7, 130.9, 131.3, 133.6, 140.1, 146.02, 169.4; HRMS (ESI-TOF) m/z [M þ Na]þ calcd for C19H21F3N2O 373.1498; found 373.1508.

[2]

[3]

[4]

[5]

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