Camphorsulfonic Acid-Mediated One-Pot Tandem Consecutive via the Ugi Four-Component Reaction for the Synthesis of Functionalized Indole and 2-Quinolone Derivatives by Switching Solvents.

A camphorsulfonic acid-mediated one-pot tandem consecutive approach was developed to synthesize functionalized indole and 2-quinolone derivatives from the Ugi four-component reaction by switching solvents. A reaction of the Ugi adduct in an aprotic solvent undergoes 5-exo-trig cyclization to form an indole ring. In a protic solvent, however, the Ugi adduct undergoes an alkyne-carbonyl metathesis reaction to form a 2-quinolone ring.

Introduction

Indoles and 2-quinolones are important classes of N-heterocyclic compounds present in several natural products[1] and biologically active compounds.[2] In particular, indoles are classified as “privileged structures” in drug discovery.[3] Thus, the development of synthetic methods of indoles has attracted widespread interest from medicinal and organic chemists over the years. The classical methods for indoles are well-known named reactions,[4] including Fischer,[5] Bischler,[6] Reissert,[7] Madelung,[8] Sundberg,[9] Bartoli,[10] and Fukuyama.[11] Recently, substituted indoles were prepared from the inter- or intramolecular cycloaddition reactions using diverse functionalized starting materials in the presence of transition-metal complexes[12] or under transition-metal-free conditions.[13] The functionalized 2-quinolone core was also synthesized using classical procedures, including acid-catalyzed Knorr synthesis,[14] base-catalyzed Friedlander synthesis,[15] Ugi–Knoevenagel reaction,[16] enzymatic synthesis,[17] and transition-metal-catalyzed reactions.[18]

On the other hand, numerous synthetic procedures have been reported for indoles and 2-quinolone core compounds. Despite these established methodologies, the development of cost-effective, short synthetic routes with readily available starting materials and metal-free, environmentally friendly approaches is desirable. In this manner, isocyanide-based multicomponent reactions (IMCRs) are a better prospect.[19] Among IMCRs, Ugi four-component reactions (U-4CRs) are a highly efficient and versatile synthetic strategy for the preparation of functionalized nitrogen heterocyclic compounds.[20] The Ugi adduct contains different active sites, such as (i) a carbonyl group, (ii) an alkyne moiety for nucleophilic or electrophilic addition, and (iii) an acidic C(sp3)–H proton. Our previous work described the post-Ugi transformation for the synthesis of 2-quinolone[20a] and 2,5-diketopiperazine.[21] In continuation of the study of Ugi adduct, we have interestingly used the Bronsted acids, resulting in five-and six-membered heterocycles by switching aprotic to protic solvents, respectively. These interesting results encouraged us to investigate further and report herein the synthesis of functionalized indole and 2-quinolone scaffolds using the Ugi-4CR adduct (Scheme ).

Scheme 1

One-Pot Synthesis of Indole and 2-Quinolone Derivatives via Single Ugi Adduct by the Solvent Switch

Results and Discussion

Our study begins with the preparation of Ugi adduct 5aaa using the previously reported procedure.[20a]Table lists the corresponding results. We started our initial screening with various neat carboxylic acids, but the results were disappointing (entries 1–4). In formic acid, an unidentified polar byproduct formed, and in TFA, cleavage of the amide bond of Ugi adduct 5aaa occurred.[20a] On the other hand, using a combination of carboxylic acids with 1,2-dichloroethane (DCE) (entries 5–8), the best yield (57%) was obtained with formic acid (entry 8).

Table 1

Optimization Conditions for Indole and 2-Quinolone Derivatives from the Ugi Adduct 5aaaa

				yield (%)b
entry	reagents/solvents	T (°C)	time (h)	6aaa	7aaa
1	AcOH	120	72	28
2	propanoic acid	120	72	24
3	formic acid	120	72	trace
4	TFA	100	5
5	AcOH/DCE (1:1)	120	72	34
6	AcOH/DCE (2:1)	120	72	42
7	PrOH/DCE (2:1)	120	72	46
8	HCOOH/DCE (2:1)	120	72	57
9	HCOOH/MeOH (2:1)	120	24	69
10	HCOOH/EtOH (2:1)	120	24	32
11	HCOOH/CH3CN (2:1)	120	24	19
12	HCOOH/IPA (2:1)	120	24	47
13	HCOOH/dioxane (2:1)	120	24	65
14	HCOOH/DMF (2:1)	120	24	62
15	pTSA (1.1 equiv)/DCE	120	96	74
16	CSA (1.1 equiv)/DCE	120	72	80
17	pTSA (1.1 equiv)/PhCl	140	20	86
18	CSA (1.1 equiv)/PhCl	140	20	98
19	CSA (1.1 equiv)/toluene	140	20	73
20	CSA (1.1 equiv)/dioxane	120	72	53
21	CSA (1.1 equiv)/MeOH	120	20		51
22	pTSA (1.1 equiv)/MeOH	120	20		43
23	CSA (1.1 equiv)/MeOH	120	96		87
24	pTSA (1.1 equiv)/MeOH	120	96		74
25	CSA (1.1 equiv)/EtOH	120	96		66
26	CSA (1.1 equiv)/propanol	120	96		52
27	CSA (1.1 equiv)/butanol	120	96		47
28	H2SO4 (1.1 equiv)/MeOH	120	72		62

Reaction conditions: reaction run at a concentration of 0.05 M.

Isolated yields.

The next screening was with formic acid and different solvents (entries 9–14). Among them, MeOH gave 69% yield (entry 9). Better results were obtained using sulfonic acids rather than carboxylic acids, such as p-toluenesulfonic acid (pTSA) and CSA; among them, CSA in DCE at 120 °C gave 80% yield over 3 days (entries 15 and 16). Subsequently, PhCl was then used at 140 °C to improve the yield and reduce the reaction time, which provided excellent yield for both pTSA and CSA in 86 and 98% over 20 h, respectively (entries 17 and 18). CSA did not give an attractive yield in toluene and 1,4-dioxane compared to PhCl (entries 19 and 20).

Surprisingly, using a protic solvent, such as MeOH, both pTSA and CSA gave the ACM product, 2-quinolone 7aaa, instead of the indole derivatives (entries 21 and 22). In particular, CSA in MeOH gave a high yield over 4 days (entry 23). Other protic solvents, such as EtOH, propanol, and butanol (entries 25–27), gave the corresponding ester derivatives of 2-quinolone 7aaa and a lower yield than MeOH. Eventually, H2SO4 (1.1 equiv) in MeOH gave the ACM product 7aaa in 62% yield. The optimal conditions for indole and 2-quinolone were CSA in PhCl at 140 °C for 20 h (entry 18) and CSA in MeOH for 4 days (entry 23), respectively.

The optimized reaction conditions were then applied to the synthesis of indole and 2-quinolone derivatives in a one-pot approach via the Ugi adduct. The corresponding results are presented in Tables and 3. Table lists the substrate scope of the indole derivatives from commercially available aldehydes (2a-y) with 2′-aminoacetophenone (1a) or 2′-aminobenzophenone (1b), aromatic substituted or aliphatic propiolic acid derivatives (the aromatic substituted phenylpropiolic acids (4b, c-d) were synthesized from commercially available terminal alkyne; see the Supporting Information), and cyclohexylisocyanide (3a). First, all four components were mixed in EtOH. After forming the Ugi adduct in 16 h, EtOH was concentrated and dried well. The reaction conditions in Table , entry 18, were then applied.

Table 2

One-Pot Synthesis of Indole Derivatives via Ugi-4CR

Table 3

One-Pot Synthesis of 2-Quinolone Derivatives via Ugi-4CR

However, 6aaa was obtained in low yield in the one-pot strategy using 1.1 equiv of CSA. The equiv of CSA was manipulated to obtain the best result (Supporting Information). The use of 2.0 equiv of CSA gave 6aaa and 6baa in 93 and 85% yields, respectively, in a one-pot approach. The molecular structures of 6aaa and 6baa were further confirmed by single-crystal X-ray diffraction analysis (Figure ). Next, we studied the substituent effects at the ortho, meta, and para benzaldehydes (2b-s). The steric effect of the ortho-positioned electron-donating group (EDG) or electron-withdrawing group (EWG) benzaldehyde derivatives resulted in a lower yield than the corresponding meta- and para-positioned derivatives, excluding the ortho-F derivative 6aha.

Figure 1

Crystal structure of 6aaa (CCDC-2052455) and 6baa (CCDC-2052474).

Unfortunately, the indole derivatives of ortho-CN 6aqa in the substrate scope of 2′-aminoacetophenone (1a), and methyl 6bba, and fluoro 6bha in the substrate scope of 2′-aminobenzophenone (1b) could not be isolated. Multiple unidentified byproducts formed, and no intermediates, such as the Ugi adduct, were isolated. 2,5-Dimethyl 6ata and 2,5-dimethoxy 6aua benzaldehyde derivatives were obtained in 93 and 95% yields, respectively.

A strong EWG at the para position of the benzaldehyde derivatives resulted in low yields, such as para-CN 6asa (56%) and para-CF36awa (46%), 6bwa (29%), respectively. The tert-butyl 6ava (93%), biphenyl 6axa (94%), and naphthaldehyde 6aya (89%) derivatives showed excellent yield. The para-positioned EDG and EWG at the phenylpropiolic acid did not affect the formation of indoles, such as tert-butyl 6aab (91%) and CF36aad (94%), respectively.

However, the yield of the aliphatic propiolic acid derivative 6aae decreased to 75%. Other carboxylic acids were also investigated under the same optimized conditions. The reaction of benzoic acid and ortho-halogenated benzoic acids and acetic acid derivatives 6aaf–6aai produced lower yields (24–43%) than the aliphatic or aromatic propiolic acid.

2-Quinolone analogues were next examined, and the corresponding results are presented in Table . In the one-pot approach, 2.5 equiv of CSA in MeOH over 4 days was the best condition to synthesize the 2-quinolone derivative 7aaa (75%) (Supporting Information). The structure of 7aaa was further confirmed by single-crystal X-ray diffraction analysis (Table ).

The steric hindrance of ortho-positioned EDG or EWG benzaldehydes plays an important role in the ACM reactions, which produced a higher yield than at the meta and para positions. The Thorpe-Ingold effects can explain these experimental results (Supporting Information). In contrast, the meta-F benzaldehyde derivative 7aia gave the highest yield, 96%, among the phenylpropiolic acids, which Thorpe-Ingold effects could not explain. In a previous report, the para-positioned EDG at the phenylpropiolic acid gave the best yield,[20a] which reflects on 7aec (94%) and 7ahc (96%).

The para-positioned EWG at the phenylpropiolic acid gave no ACM products, such as 7aed and 7ahd, even though a higher temperature and longer reaction time were used. The EWG suppressed the nucleophilicity of the alkyne toward the carbonyl group. In that case, the intermediate of the Ugi adduct (53–60%) was isolated, and the amide bond of the Ugi adduct was cleaved (2.0–3.5%) with the cyclohexyl amide group intact. These results showed that methanolysis of cyclohexyl amide occurs after the ACM reaction or simultaneously, and the methanolysis under these reaction conditions could not be controlled for all other substrates.

Scheme presents a plausible mechanism for the indole and 2-quinolone from the Ugi adduct 5aaa based on the experimental results. In general, the Bronsted acids dissociate into proton H+ and its conjugate base. However, in the nonpolar aprotic solvent, the charge separation is not very effective. Therefore, the CSA approaches the Ugi adduct through H-bonding, resulting in the conjugate base of CSA formed simultaneously, abstracting the sp3 acidic proton, stabilizing as enol II. Subsequent nucleophilic attack on the carbonyl carbon formed a five-membered indoline ring III.[21,22] Finally, the desired product 6aaa was produced by the elimination of water and cyclohexyl isocyanate through a six-membered transition state. The water molecule was eliminated first when R=CH3, resulting in the formation of an exocyclic double bond 6aga-int IV, which was further confirmed by single-crystal X-ray diffraction analysis (Figure ). Next, the indole derivative was formed through a six-membered transition state.

Scheme 2

Plausible Mechanism of the Formation of Indole and 2-Quinolone Derivatives

Figure 2

Exocyclic double-bond intermediate 6aga-int IV and crystal structure CCDC-2052490.

In the polar protic solvents, the charge separation of CSA is favored. The dissociated conjugate base of CSA was strongly solvated by methanol through hydrogen bonding, and the protons protonated the carbonyl oxygen V, which enhanced the electrophilicity of the carbonyl carbon. Subsequent intramolecular nucleophilic addition from the alkyne resulted in the formation of cation, which was neutralized with methanol VI. The protonation of tertiary benzylic alcohol was eliminated as loss of water and the formation of oxonium ion VII. The eliminated water attacked the oxonium ion to give the ACM product. Simultaneously, cyclohexyl amide was cleaved by methanolysis through the protonation of carbonyl oxygen, resulting in the formation of the desired product 7aaa.[23]

Conclusions

In conclusion, we have developed a method to synthesize five- and six-membered nitrogen-containing heterocycles, such as indole and 2-quinolone derivatives. The strategy involved a metal-free, one-pot reaction via an Ugi adduct with camphorsulfonic acid by switching the solvent from readily available starting materials. Moreover, easy workup and purification, air and moisture tolerance, and good to excellent yields were achieved.

Experimental Section

General Information

All reagents were commercial and used without further purification unless otherwise indicated. All reactions were monitored by TLC using precoated aluminum sheets of silica gel 60 F254, which were analyzed using iodine, UV light, and alkaline KMnO4. Melting points were recorded in open capillary tubes using a melting point apparatus MP-1D (Fargo Instruments) and are uncorrected. Infrared spectra were recorded using a PerkinElmer FT/IR spectrometer. 1H NMR spectra and 13C NMR spectra were obtained at 400 and 101 MHz, respectively, using a Bruker NMR spectrometer. Chemical shifts are expressed in parts per million (ppm) and referenced to CDCl3 (δ = 7.26 ppm for 1H and 77.16 ppm for 13C) TMS as the internal standard. Signal description: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplet, qd = quartet of doublet, qt = quartet of triplet, td = triplet of doublet, tt = triplet of triplet, ddd = doublet of doublet of doublet, and tdd = triplet of doublet of doublet.

Typical Procedure for the Synthesis of 1-(3-Methyl-2-phenyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aaa)

To a stirred solution of 2′-aminoacetophenone (100 mg, 0.740 mmol) and benzaldehyde (118 mg, 1.112 mmol) in EtOH (2.0 mL) was added 3-phenylpropiolic acid (119 mg, 0.814 mmol) at room temperature. After 30 min stirring, cyclohexylisocyanide (0.101 mL, 0.814 mmol) was added, and the resulting reaction mixture was stirred for 16 h. TLC showed the formation of Ugi product. Then, the reaction mixture was concentrated and dried well. Then, PhCl (15.0 mL, 0.05 M) and CSA (343 mg, 1.480 mmol) were added and heated to 140 °C for 20 h. After completion of the reaction, the reaction mixture was concentrated and dried well. The crude was purified by silica gel (230–400 mesh) column chromatography (0–10% EtOAc in hexanes) to afford 6aaa, 230 mg, 93%; yellow solid; mp 148–150 °C; 1H NMR (400 MHz, CDCl3) δ 8.55 (dt, J = 8.4, 0.9 Hz, 1H), 7.58–7.54 (m, 1H), 7.53–7.49 (m, 2H), 7.49–7.32 (m, 6H), 7.28–7.22 (m, 2H), 7.11–7.05 (m, 2H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.9, 136.7, 135.1, 133.0, 132.6, 131.1, 130.9, 130.4, 128.5, 128.3, 128.2, 125.7, 124.4, 119.8, 119.1, 118.9, 116.7, 96.3, 83.7, 9.4; IR (KBr) 3063, 2978, 2923, 2892, 2224, 2202, 1647, 1615, 1594, 1490, 1454, 1444, 1356, 1328, 1190, 1180, 1155, 1070, 953, 921, 817, 758, 746, 702, 684 cm–1; LRMS-ESI (m/z): 358.23 [M + Na]+; HRMS (TOF-ES) (m/z): 336.1388 [M + H]+ calcd for C24H18NO, found 336.1393.

1-(3-Methyl-2-(o-tolyl)-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aba)

Chromatography purification (0–10% EtOAc in hexanes) gave 101 mg, 39%; pale yellow solid; mp 105–107 °C; 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 7.8 Hz, 1H), 7.58–7.53 (m, 1H), 7.45–7.32 (m, 4H), 7.29–7.22 (m, 5H), 7.15–7.07 (m, 2H), 2.23 (s, 3H), 2.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.7, 139.2, 136.4, 134.5, 133.1, 132.1, 131.8, 131.0, 130.4, 130.1, 129.4, 128.2, 125.8, 125.5, 124.4, 119.9, 118.84, 118.75, 117.3, 95.4, 82.7, 20.3, 9.2; IR (KBr) 3064, 3035, 3019, 2973, 2917, 2860, 2202, 1652, 1490, 1456, 1392, 1359, 1325, 1190, 1069, 952, 819, 749, 688, 630 cm–1; LRMS-ESI (m/z): 372.69 [M + Na]+; HRMS (TOF-ES) (m/z): 350.1545 [M + H]+ calcd for C25H20NO, found 350.1546.

1-(3-Methyl-2-(m-tolyl)-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aca)

Chromatography purification (0–10% EtOAc in hexanes) gave 223 mg, 86%; pale brown gum; 1H NMR (400 MHz, CDCl3) δ 8.57–8.49 (m, 1H), 7.62–7.51 (m, 1H), 7.43 (dd, J = 7.3, 1.5 Hz, 1H), 7.40 (dd, J = 3.5, 1.6 Hz, 1H), 7.38–7.35 (m, 1H), 7.35–7.30 (m, 3H), 7.29–7.22 (m, 2H), 7.17–7.12 (m, 1H), 7.11–7.07 (m, 2H), 2.37 (s, 3H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.0, 137.8, 136.8, 135.3, 132.9, 132.5, 131.7, 130.9, 130.4, 129.3, 128.3, 128.2, 128.1, 125.6, 124.4, 119.9, 118.9, 118.8, 116.7, 96.0, 83.7, 21.5, 9.4; IR (KBr) 3051, 2917, 2857, 2202, 1654, 1613, 1596, 1490, 1474, 1456, 1392, 1356, 1323, 1267, 1201, 1188, 1134, 1070, 954, 825, 792, 783, 752, 702, 752, 702, 688, 631, 543, 535 cm–1; LRMS-ESI (m/z): 350.47 [M + H]+; HRMS (TOF-ES) (m/z): 350.1545 [M + H]+ calcd for C25H20NO, found 350.1542.

1-(3-Methyl-2-(p-tolyl)-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6ada)

Chromatography purification (0–10% EtOAc in hexanes) gave 232 mg, 90%; pale yellow solid; mp 92–94 °C; 1H NMR (400 MHz, CDCl3) δ 8.57–8.52 (m, 1H), 7.57–7.52 (m, 1H), 7.42 (dd, J = 7.3, 1.5 Hz, 1H), 7.40–7.36 (m, 3H), 7.36–7.32 (m, 1H), 7.28–7.21 (m, 4H), 7.10–7.05 (m, 2H), 2.32 (s, 3H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.9, 138.5, 136.7, 135.3, 132.8, 131.2, 131.0, 130.3, 129.6, 129.0, 128.2, 125.5, 124.4, 120.1, 118.8, 118.7, 116.9, 96.1, 83.6, 21.4, 9.4; IR (KBr) 3063, 3040, 2917, 2858, 2212, 2203, 1648, 1608, 1593, 1511, 1489, 1454, 1442, 1390, 1355, 1333, 1310, 1263, 1242, 1190, 1177, 1154, 1137, 1067, 1029, 1017, 950, 829, 760, 750, 691, 647, 618, 534, 506 cm–1; LRMS-ESI (m/z): 372.29 [M + Na]+; HRMS (TOF-ES) (m/z): 350.1545 [M + H]+ calcd for C25H20NO, found 350.1547.

1-(2-(2-Methoxyphenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aea)

Chromatography purification (0–10% EtOAc in hexanes) gave 176 mg, 65%; yellow solid; mp 67–69 °C; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.1 Hz, 1H), 7.57–7.50 (m, 1H), 7.44–7.37 (m, 2H), 7.37–7.30 (m, 3H), 7.24 (t, J = 7.4 Hz, 2H), 7.12–7.06 (m, 3H), 6.89 (d, J = 8.2 Hz, 1H), 3.77 (s, 3H), 2.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 158.6, 152.0, 136.5, 133.0, 132.3, 132.0, 131.0, 130.7, 130.3, 128.6, 128.1, 125.4, 124.0, 121.4, 120.6, 119.9, 118.8, 116.7, 110.7, 93.3, 83.4, 55.6, 9.6; IR (KBr) 3066, 3055, 3033, 2966, 2936, 2915, 2858, 2835, 2202, 1649, 1594, 1490, 1453, 1358, 1328, 1250, 1112, 1025, 952, 755, 749, 688 cm–1; LRMS-ESI (m/z): 388.60 [M + Na]+; HRMS (TOF-ES) (m/z): 366.1494 [M + H]+ calcd for C25H20NO2, found 366.1498.

1-(2-(3-Methoxyphenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6afa)

Chromatography purification (0–10% EtOAc in hexanes) gave 211 mg, 78%; pale brown gum; 1H NMR (400 MHz, CDCl3) δ 8.52 (dt, J = 8.2, 0.8 Hz, 1H), 7.58–7.52 (m, 1H), 7.43 (dd, J = 7.3, 1.4 Hz, 1H), 7.39 (dd, J = 4.0, 1.5 Hz, 1H), 7.38–7.31 (m, 2H), 7.29–7.23 (m, 2H), 7.16–7.11 (m, 2H), 7.08 (ddd, J = 7.5, 1.6, 1.0 Hz, 1H), 7.05 (dd, J = 2.6, 1.5 Hz, 1H), 6.86 (ddd, J = 8.4, 2.7, 1.0 Hz, 1H), 3.78 (s, 3H), 2.20 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.5, 151.9, 136.8, 135.0, 134.0, 132.9, 130.8, 130.4, 129.3, 128.2, 125.7, 124.4, 123.8, 120.0, 119.1, 118.9, 116.8, 116.7, 114.2, 95.8, 83.6, 55.4, 9.5; IR (KBr) 3065, 2937, 2834, 2202, 1719, 1654, 1610, 1597, 1575, 1490, 1457, 1429, 1392, 1355, 1325, 1286, 1256, 1217, 1133, 1069, 1049, 955, 821, 788, 753, 722, 698, 687, 635, 559, 535 cm–1; LRMS-ESI (m/z): 366.28 [M + H]+; HRMS (TOF-ES) (m/z): 366.1494 [M + H]+ calcd for C25H20NO2, found 366.1495.

1-(2-(4-Methoxyphenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aga)

Chromatography purification (0–10% EtOAc in hexanes) gave 203 mg, 75%; pale yellow solid; mp 122–124 °C; 1H NMR (400 MHz, CDCl3) δ 8.58–8.50 (m, 1H), 7.58–7.49 (m, 1H), 7.44–7.32 (m, 5H), 7.29–7.22 (m, 2H), 7.15–7.09 (m, 2H), 6.98–6.91 (m, 2H), 3.74 (s, 3H), 2.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.9, 152.0, 136.6, 135.1, 132.9, 132.6, 130.9, 130.3, 128.2, 125.5, 124.7, 124.4, 120.2, 118.7, 118.6, 116.9, 113.9, 96.3, 83.6, 55.3, 9.4; IR (KBr) 2960, 2193, 1641, 1615, 1598, 1508, 1490, 1444, 1394, 1361, 1325, 1293, 1264, 1246, 1186, 1178, 1133, 1071, 1032, 1021, 951, 838, 788, 755, 719, 685, 626, 531 cm–1; LRMS-ESI (m/z): 388.34 [M + Na]+; HRMS (TOF-ES) (m/z): 366.1494 [M + H]+ calcd for C25H20NO2, found 366.1496.

1-(2-(2-Fluorophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aha)

Chromatography purification (0–10% EtOAc in hexanes) gave 185 mg, 71%; pale yellow solid; mp 168–170 °C; 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 8.2 Hz, 1H), 7.59–7.54 (m, 1H), 7.50–7.40 (m, 2H), 7.40–7.30 (m, 3H), 7.29–7.22 (m, 3H), 7.18–7.08 (m, 3H), 2.15 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.0 (d, JC–F = 248.1 Hz), 151.4, 136.8, 132.9, 132.8 (d, JC–F = 2.7 Hz), 130.9 (d, JC–F = 8.1 Hz), 130.7, 130.5, 128.9, 128.3, 125.9, 124.4, 124.1 (d, JC–F = 3.7 Hz), 120.69 (d, JC–F = 15.7 Hz), 120.65, 119.7, 119.0, 116.8, 115.8 (d, JC–F = 21.6 Hz), 94.9, 83.1, 9.4; IR (KBr) 3082, 3063, 3036, 2923, 2854, 2203, 1647, 1490, 1453, 1393, 1356, 1325, 1219, 1102, 1070, 952, 801, 757, 751, 685, cm–1; LRMS-ESI (m/z): 376.68 [M + Na]+; HRMS (TOF-ES) (m/z): 354.1294 [M + H]+ calcd for C24H17FNO, found 354.1292.

1-(2-(3-Fluorophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aia)

Chromatography purification (0–10% EtOAc in hexanes) gave 189 mg, 72%; pale yellow solid; mp 80–82 °C; 1H NMR (400 MHz, CDCl3) δ 8.55–8.50 (m, 1H), 7.56 (ddd, J = 7.5, 1.5, 0.7 Hz, 1H), 7.47–7.43 (m, 1H), 7.42–7.35 (m, 3H), 7.31–7.25 (m, 3H), 7.23 (ddd, J = 9.4, 2.6, 1.5 Hz, 1H), 7.18–7.12 (m, 2H), 7.01 (tdd, J = 8.5, 2.6, 1.1 Hz, 1H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6 (d, JC–F = 246.7 Hz), 151.6, 136.8, 134.8 (d, JC–F = 8.4 Hz), 133.7 (d, JC–F = 2.2 Hz), 132.7, 130.7, 130.6, 129.9, 129.8, 128.4, 127.0 (d, JC–F = 3.0 Hz), 126.0, 124.6, 119.8, 119.7, 119.1, 117.9 (d, JC–F = 21.8 Hz), 116.7, 115.5 (d, JC–F = 20.9 Hz), 96.1, 83.6, 9.4; IR (KBr) 6065, 2204, 1655, 1615, 1596, 1584, 1570, 1490, 1456, 1442, 1389, 1352, 1323, 1262, 1254, 1199, 1186, 1150, 1130, 1076, 1066, 954, 914, 796, 754, 670, 687, 534, 470 cm–1; LRMS-ESI (m/z): 354.20 [M + H]+; HRMS (TOF-ES) (m/z): 354.1294 [M + H]+ calcd for C24H17FNO, found 354.1296.

1-(2-(4-Fluorophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aja)

Chromatography purification (0–10% EtOAc in hexanes) gave 210 mg, 80%; pale yellow solid; mp 154–156 °C; 1H NMR (400 MHz, CDCl3) δ 8.54 (dt, J = 8.2, 0.9 Hz, 1H), 7.58–7.53 (m, 1H), 7.50–7.44 (m, 2H), 7.43–7.34 (m, 3H), 7.32–7.26 (m, 2H), 7.16–7.09 (m, 4H), 2.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.9 (d, JC–F = 248.6 Hz), 151.7, 136.6, 134.0, 133.0 (d, JC–F = 8.2 Hz), 132.7, 130.7, 130.6, 128.6 (d, JC–F = 3.5 Hz), 128.4, 125.8, 124.5, 119.7, 119.4, 118.9, 116.8, 115.4 (d, JC–F = 21.7 Hz), 96.5, 83.5, 9.4; IR (KBr) 3063, 2214, 2202, 1647, 1560, 1588, 1508, 1489, 1453, 1350, 1326, 1219, 1188, 1156, 1135, 1066, 952, 841, 797, 757, 688, 647, 617, 534, 515 cm–1; LRMS-ESI (m/z): 376.10 [M + Na]+; HRMS (TOF-ES) (m/z): 354.1294 [M + H]+ calcd for C24H17FNO, found 354.1298.

1-(2-(2-Chlorophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aka)

Chromatography purification (0–10% EtOAc in hexanes) gave 98 mg, 36%; yellow solid; mp 149–151 °C; 1H NMR (400 MHz, CDCl3) δ 8.62–8.57 (m, 1H), 7.63–7.57 (m, 1H), 7.52–7.43 (m, 3H), 7.43–7.34 (m, 3H), 7.32–7.26 (m, 3H), 7.24–7.17 (m, 2H), 2.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.3, 136.4, 136.1, 133.1, 132.8, 132.0, 131.9, 130.7, 130.44, 130.41, 129.7, 128.2, 126.7, 125.9, 124.4, 120.2, 119.8, 119.0, 117.0, 94.8, 83.0, 9.3; IR (KBr) 3062, 2957, 2923, 2854, 2200, 1656, 1490, 1452, 1392, 1357, 1325, 1194, 1140, 1075, 952, 816, 751, 688, 629 cm–1; LRMS-ESI (m/z): 392.61 [M + Na]+; HRMS (TOF-ES) (m/z): 370.0999 [M + H]+ calcd for C24H17ClNO, found 370.1002.

1-(2-(3-Chlorophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6ala)

Chromatography purification (0–10% EtOAc in hexanes) gave 206 mg, 75%; yellow solid; mp 85–87 °C; 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.1 Hz, 1H), 7.59–7.54 (m, 1H), 7.52 (s, 1H), 7.47–7.41 (m, 1H), 7.41–7.33 (m, 4H), 7.32–7.23 (m, 3H), 7.19–7.11 (m, 2H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.6, 136.8, 134.6, 134.3, 133.5, 132.8, 130.8, 130.6, 129.6, 129.4, 128.6, 128.4, 126.1, 124.6, 119.9, 119.6, 119.1, 116.7, 96.3, 83.6, 9.5; IR (KBr) 3062, 3052, 3035, 2921, 2855, 2203, 1656, 1490, 1453, 1390, 1355, 1322, 1192, 1069, 953, 819, 752, 688 cm–1; LRMS-ESI (m/z): 392.53 [M + Na]+; HRMS (TOF-ES) (m/z): 370.0999 [M + H]+ calcd for C24H17ClNO, found 370.0999.

1-(2-(4-Chlorophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6ama)

Chromatography purification (0–10% EtOAc in hexanes) gave 224 mg, 82%; pale yellow solid; mp 128–130 °C; 1H NMR (400 MHz, CDCl3) δ 8.55 (dt, J = 8.4, 0.9 Hz, 1H), 7.59–7.51 (m, 1H), 7.48–7.35 (m, 7H), 7.33–7.28 (m, 2H), 7.14–7.08 (m, 2H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.6, 136.7, 134.8, 133.8, 132.7, 132.5, 131.1, 130.7, 130.6, 128.6, 128.5, 125.9, 124.6, 119.6, 119.6, 119.0, 116.9, 96.6, 83.6, 9.4; IR (KBr) 3068, 3051, 2920, 2204, 1649, 1590, 1574, 1489, 1451, 1442, 1387, 1352, 1325, 1305, 1262, 1243, 1189, 1154, 1154, 1138, 1090, 1066, 1028, 1009, 948, 839, 827, 753, 724, 716, 685, 534, 506 cm–1; LRMS-ESI (m/z): 392.23 [M + Na]+; HRMS (TOF-ES) (m/z): 370.0999 [M + H]+ calcd for C24H17ClNO, found 370.1000.

1-(2-(2-Bromophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6ana)

Chromatography purification (0–10% EtOAc in hexanes) gave 117 mg, 38%; brown solid; mp 129–131 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.59–7.55 (m, 1H), 7.48–7.41 (m, 2H), 7.41–7.34 (m, 3H), 7.30–7.27 (m, 1H), 7.26–7.24 (m, 1H), 7.22–7.12 (m, 3H), 2.07 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.2, 136.3, 134.1, 133.6, 133.3, 132.83, 132.81, 130.7, 130.6, 130.4, 128.2, 127.3, 126.6, 125.9, 124.5, 120.0, 119.9, 119.1, 117.2, 94.9, 83.1, 9.3; IR (KBr) 3062, 3055, 3033, 3018, 2919, 2854, 2200, 1654, 1490, 1452, 1392, 1359, 1325, 1192, 1159, 1139, 1072, 1020, 952, 816, 750, 688, 628 cm–1; LRMS-ESI (m/z): 436.70 [M + Na]+; HRMS (TOF-ES) (m/z): 414.0494 [M + H]+ calcd for C24H17BrNO, found 414.0497.

1-(2-(3-Bromophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aoa)

Chromatography purification (0–10% EtOAc in hexanes) gave 214 mg, 70%; brown solid; mp 109–111 °C; 1H NMR (400 MHz, CDCl3) δ 8.55–8.49 (m, 1H), 7.68 (t, J = 1.8 Hz, 1H), 7.56 (dd, J = 7.1, 1.5 Hz, 1H), 7.45–7.36 (m, 5H), 7.32–7.27 (m, 3H), 7.19–7.14 (m, 2H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.6, 136.8, 134.8, 133.6, 133.4, 132.8, 131.5, 130.64, 130.6, 129.84, 129.82, 128.4, 126.1, 124.6, 122.4, 120.0, 119.6, 119.1, 116.7, 96.4, 83.6, 9.5; IR (KBr) 3064, 3056, 3022, 2926, 2855, 2203, 1719, 1656, 1559, 1453, 1390, 1355, 1322, 1192, 1158, 1138, 1069, 953, 818, 754, 720, 688 cm–1; LRMS-ESI (m/z): 436.53 [M + Na]+; HRMS (TOF-ES) (m/z): 414.0494 [M + H]+ calcd for C24H17BrNO, found 414.0493.

1-(2-(4-Bromophenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6apa)

Chromatography purification (0–10% EtOAc in hexanes) gave 255 mg, 83%; yellow solid; mp 88–90 °C; 1H NMR (400 MHz, CDCl3) δ 8.54 (dt, J = 8.2, 0.9 Hz, 1H), 7.61–7.53 (m, 3H), 7.46–7.35 (m, 5H), 7.34–7.28 (m, 2H), 7.13–7.07 (m, 2H), 2.16 (d, J = 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 151.6, 136.8, 133.8, 132.8, 131.6, 131.5, 130.7, 130.6, 128.5, 126.0, 124.6, 123.2, 119.6, 119.0, 117.0, 96.6, 83.6, 9.4; IR (KBr) 3079, 3057, 2203, 1656, 1603, 1489, 1453, 1442, 1389, 1367, 1359, 1334, 1325, 1190, 1152, 1136, 1070, 1007, 950, 832, 758, 749, 706, 687, 534, 505 cm–1; LRMS-ESI (m/z): 436.25 [M + Na]+; HRMS (TOF-ES) (m/z): 414.0494 [M + H]+ calcd for C24H17BrNO, found 414.0496.

3-(3-Methyl-1-(3-phenylpropioloyl)-1H-indol-2-yl)benzonitrile (6ara)

Chromatography purification (0–10% EtOAc in hexanes) gave 158 mg, 59%; yellow solid; mp 164–166 °C; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 7.71 (dt, J = 7.0, 1.8 Hz, 1H), 7.61–7.49 (m, 3H), 7.48–7.36 (m, 3H), 7.31 (t, J = 7.6 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 2.18 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.1, 136.8, 135.3, 134.4, 134.0, 132.53, 132.5, 131.8, 130.9, 130.5, 129.2, 128.6, 126.4, 124.7, 120.7, 119.35, 119.3, 118.4, 116.6, 112.7, 96.4, 83.8, 9.4; IR (KBr) 3066, 3037, 2920, 2860, 2230, 2203, 1657, 1490, 1455, 1392, 1356, 1326, 1201, 1133, 1070, 956, 824, 754, 689, 634 cm–1; LRMS-ESI (m/z): 361.59 [M + H]+; HRMS (TOF-ES) (m/z): 361.1341 [M + H]+ calcd for C25H17N2O, found 361.1342.

4-(3-Methyl-1-(3-phenylpropioloyl)-1H-indol-2-yl)benzonitrile (6asa)

Chromatography purification (0–10% EtOAc in hexanes) gave 149 mg, 56%; yellow solid; mp 158–160 °C; 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 7.9 Hz, 1H), 7.74–7.68 (m, 2H), 7.64–7.59 (m, 2H), 7.59–7.55 (m, 1H), 7.49–7.36 (m, 3H), 7.36–7.28 (m, 2H), 7.14–7.04 (m, 2H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.2, 137.7, 136.9, 133.0, 132.4, 131.9, 131.5, 131.1, 130.6, 128.6, 126.5, 124.7, 120.9, 119.3, 119.2, 118.5, 116.6, 111.9, 96.4, 83.8, 9.5; IR (KBr) 3052, 2969, 2922, 2854, 2225, 2203, 1719, 1654, 1606, 1489, 1453, 1352, 1324, 1191, 1136, 1068, 950, 838, 752, 686, 613 555 cm–1; LRMS-ESI (m/z): 361.57 [M + H]+; HRMS (TOF-ES) (m/z): 361.1341 [M + H]+ calcd for C25H17N2O, found 361.1341.

1-(2-(3,5-Dimethylphenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6ata)

Chromatography purification (0–10% EtOAc in hexanes) gave 249 mg, 93%; yellow solid; mp 89–91 °C; 1H NMR (400 MHz, CDCl3) δ 8.51 (dt, J = 8.2, 0.8 Hz, 1H), 7.57–7.51 (m, 1H), 7.44–7.33 (m, 3H), 7.28–7.22 (m, 2H), 7.11–7.09 (m, 3H), 7.09–7.07 (m, 1H), 6.94–6.91 (m, 1H), 2.31 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.1, 137.7, 136.8, 135.6, 132.8, 132.4, 131.0, 130.3, 130.28, 128.9, 128.1, 125.5, 124.4, 120.1, 118.8, 118.7, 116.7, 95.8, 83.6, 21.4, 9.5; IR (KBr) 3043, 2914, 2206, 1646, 1611, 1595, 1491, 1455, 1394, 1362, 1350, 1335, 1328, 1216, 1191, 1153, 1138, 1079, 958, 914, 857, 772, 753, 743, 685, 651, 541, 532 cm–1; LRMS-ESI (m/z): 386.30 [M + Na]+; HRMS (TOF-ES) (m/z): 364.1701 [M + H]+ calcd for C26H22NO, found 364.1703.

1-(2-(3,5-Dimethoxyphenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aua)

Chromatography purification (0–10% EtOAc in hexanes) gave 277 mg, 95%; yellow gum; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 7.0, 1.6 Hz, 1H), 7.41 (td, J = 8.1, 1.6 Hz, 1H), 7.36 (td, J = 7.2, 1.4 Hz, 2H), 7.30–7.23 (m, 2H), 7.22–7.15 (m, 2H), 6.63 (d, J = 2.3 Hz, 2H), 6.37 (t, J = 2.3 Hz, 1H), 3.75 (s, 6H), 2.20 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.6, 152.0, 136.7, 135.0, 134.5, 132.8, 130.8, 130.4, 128.2, 125.7, 124.5, 120.0, 119.0, 118.96, 116.7, 109.4, 100.8, 95.4, 83.5, 55.6, 9.5; IR (KBr) 3056, 3001, 2956, 2933, 2842, 2204, 1654, 1591, 1490, 1456, 1423, 1392, 1355, 1322, 1223, 1205, 1156, 1132, 1077, 1065, 958, 851, 755, 688, 535 cm–1; LRMS-ESI (m/z): 418.48 [M + Na]+; HRMS (TOF-ES) (m/z): 396.1600 [M + H]+ calcd for C26H22NO3, found 396.1601.

1-(2-(4-(tert-Butyl)phenyl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6ava)

Chromatography purification (0–10% EtOAc in hexanes) gave 269 mg, 93%; white solid; mp 166–168 °C; 1H NMR (400 MHz, CDCl3) δ 8.53 (ddd, J = 8.1, 1.4, 0.7 Hz, 1H), 7.55 (ddd, J = 7.2, 1.7, 0.7 Hz, 1H), 7.45–7.43 (m, 4H), 7.40 (dd, J = 7.9, 1.6 Hz, 1H), 7.38 (dd, J = 7.3, 1.4 Hz, 1H), 7.36–7.30 (m, 1H), 7.24–7.19 (m, 2H), 7.09–7.05 (m, 2H), 2.19 (s, 3H), 1.24 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 152.1, 151.2, 136.8, 135.3, 132.8, 131.0, 130.8, 130.3, 129.5, 128.2, 125.5, 125.3, 124.4, 120.0, 118.9, 118.8, 116.7, 96.0, 83.6, 34.7, 31.3, 9.5; IR (KBr) 3063, 2962, 2864, 2204, 1653, 1622, 1600, 1490, 1474, 1454, 1393 1359, 1334, 1323, 1266, 1246, 1186, 1158, 1136, 1069, 1029, 844, 831, 759, 723, 759, 722, 690, 648, 635, 614, 558, 537 cm–1; LRMS-ESI (m/z): 414.33 [M + Na]+; HRMS (TOF-ES) (m/z): 392.2014 [M + H]+ calcd for C28H26NO, found 392.2017.

1-(3-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6awa)

Chromatography purification (0–10% EtOAc in hexanes) gave 138 mg, 46%; white solid; mp 142–144 °C; 1H NMR (400 MHz, CDCl3) δ 8.55 (dt, J = 8.3, 0.9 Hz, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.7 Hz, 2H), 7.57 (ddd, J = 7.5, 1.5, 0.7 Hz, 1H), 7.45 (ddd, J = 8.3, 7.3, 1.5 Hz, 1H), 7.42–7.34 (m, 2H), 7.29–7.21 (m, 2H), 7.05–6.95 (m, 2H), 2.18 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.4, 136.9, 136.6, 133.5, 132.6, 131.4, 130.8, 130.6, 130.3 (q, JC–F = 32.4 Hz), 128.4, 126.3, 125.2 (q, JC–F = 3.7 Hz), 124.7, 124.1 (q, JC–F = 272.3 Hz), 120.4, 119.3, 119.2, 116.9, 96.6, 83.6, 9.5; IR (KBr) 2978, 2893, 2194, 1646, 1619, 1597, 1492, 1456, 1445, 1396, 1362, 1320, 1267, 1248, 1192, 1188, 1169, 1156, 1136, 1122, 1108, 1065, 1025, 1014, 952, 866, 846, 840, 751, 692, 687, 636, 535 cm–1; LRMS-ESI (m/z): 426.26 [M + Na]+; HRMS (TOF-ES) (m/z): 404.1262 [M + H]+ calcd for C25H17F3NO, found 404.1266.

1-(2-([1,1′-Biphenyl]-4-yl)-3-methyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6axa)

Chromatography purification (0–10% EtOAc in hexanes) gave 285 mg, 94%; pale yellow solid; mp 141–143 °C; 1H NMR (400 MHz, CDCl3) δ 8.60–8.53 (m, 1H), 7.69–7.63 (m, 2H), 7.60–7.55 (m, 3H), 7.55–7.50 (m, 2H), 7.49–7.43 (m, 3H), 7.42–7.36 (m, 2H), 7.30–7.23 (m, 1H), 7.15–7.08 (m, 2H), 7.06–7.00 (m, 2H), 2.23 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.9, 141.5, 140.6, 136.8, 134.8, 132.8, 131.7, 131.5, 130.9, 130.3, 128.9, 128.3, 127.7, 127.3, 127.0, 125.8, 124.5, 119.8, 119.3, 118.9, 117.0, 96.5, 83.7, 9.6; IR (KBr) 3061, 3028, 2915, 2196, 1644, 1594, 1580, 1490, 1482, 1454, 1430, 1393, 1360, 1325, 1187, 1178, 1132, 1070, 1008, 948, 922, 865, 839, 812, 752, 696, 689, 648, 632, 535 cm–1; LRMS-ESI (m/z): 434.17 [M + Na]+; HRMS (TOF-ES) (m/z): 412.1701 [M + H]+ calcd for C30H22NO, found 412.1703.

1-(3-Methyl-2-(naphthalen-2-yl)-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6aya)

Chromatography purification (0–10% EtOAc in hexanes) gave 255 mg, 89%; pale yellow solid; mp 129–131 °C; 1H NMR (400 MHz, CDCl3) δ 8.59 (dt, J = 8.3, 0.8 Hz, 1H), 8.03–7.98 (m, 1H), 7.94–7.88 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.84–7.79 (m, 1H), 7.61–7.55 (m, 2H), 7.55–7.50 (m, 2H), 7.47–7.42 (m, 1H), 7.40 (td, J = 7.4, 1.3 Hz, 1H), 7.19–7.12 (m, 1H), 6.96–6.87 (m, 2H), 6.53–6.44 (m, 2H), 2.23 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.9, 136.9, 135.1, 133.4, 133.2, 132.5, 131.0, 130.2, 130.11, 130.08, 128.9, 128.3, 128.0, 127.8, 127.7, 126.8, 126.6, 125.8, 124.5, 119.5, 119.4, 119.0, 117.0, 96.2, 83.6, 9.5; IR (KBr) 3053, 3034, 2201, 1653, 1594, 1489, 1473, 1453, 1444, 1382, 1356, 1344, 1321, 1307, 1268, 1228, 1195, 1190, 1069, 1018, 960, 944, 905, 826, 810, 792, 759, 750, 718, 685, 543, 539 cm–1; LRMS-ESI (m/z): 408.16 [M + Na]+; HRMS (TOF-ES) (m/z): 386.1545 [M + H]+ calcd for C28H20NO, found 386.1544.

3-(4-(tert-Butyl)phenyl)-1-(3-methyl-2-phenyl-1H-indol-1-yl)prop-2-yn-1-one (6aab)

Chromatography purification (0–10% EtOAc in hexanes) gave 263 mg, 91%; pale yellow solid; mp 55–57 °C; 1H NMR (400 MHz, CDCl3) δ 8.57–8.51 (m, 1H), 7.57–7.53 (m, 1H), 7.53–7.45 (m, 4H), 7.44–7.34 (m, 3H), 7.30–7.24 (m, 2H), 7.05–6.98 (m, 2H), 2.19 (s, 3H), 1.29 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 154.2, 152.1, 136.8, 135.2, 133.1, 132.7, 131.1, 130.9, 128.5, 128.3, 125.6, 125.3, 124.3, 119.0, 118.9, 116.8, 116.7, 97.0, 83.5, 35.1, 31.2, 9.5; IR (KBr) 3438, 3053, 2963, 2866, 2199, 1654, 1602, 1506, 1455, 1392, 1355, 1325, 1268, 1187, 1157, 1138, 1106, 1069, 1016, 952, 837, 816, 748, 699, 564 cm–1; LRMS-ESI (m/z): 414.30 [M + Na]+; HRMS (TOF-ES) (m/z): 392.2014 [M + H]+ calcd for C28H26NO, found 392.2018.

1-(3-Methyl-2-phenyl-1H-indol-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one (6aad)

Chromatography purification (0–10% EtOAc in hexanes) gave 280 mg, 94%; pale yellow solid; mp 131–133 °C; 1H NMR (400 MHz, CDCl3) δ 8.55–8.50 (m, 1H), 7.59–7.53 (m, 1H), 7.53–7.48 (m, 4H), 7.48–7.31 (m, 5H), 7.16 (d, J = 8.1 Hz, 2H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.4, 136.7, 134.9, 133.1, 132.6, 131.9 (q, JC–F = 32.9 Hz), 131.3, 130.9, 128.7, 128.4, 125.9, 125.1 (d, JC–F = 3.8 Hz), 124.7, 123.7 (q, JC–F = 272.5 Hz), 122.3, 119.6, 119.0, 116.9, 94.0, 84.9, 9.4; IR (KBr) 3055, 2974, 2944, 2920, 2223, 2204, 1655, 1616, 1596, 1476, 1455, 1443, 1395, 1363, 1336, 1319, 1268, 1246, 1186, 1169, 1159, 1121, 1105, 1064, 1015, 952, 925, 839, 823, 753, 739, 704, 653, 645, 596, 527 cm–1; LRMS-ESI (m/z): 426.31 [M + Na]+; HRMS (TOF-ES) (m/z): 404.1262 [M + H]+ calcd for C25H17F3NO, found 404.1261.

1-(3-Methyl-2-phenyl-1H-indol-1-yl)but-2-yn-1-one (6aae)

Chromatography purification (0–10% EtOAc in hexanes) gave 152 mg, 75%; yellow gum; 1H NMR (400 MHz, CDCl3) δ 8.52–8.47 (m, 1H), 7.55–7.51 (m, 1H), 7.50–7.47 (m, 1H), 7.46–7.42 (m, 3H), 7.41–7.32 (m, 3H), 2.14 (s, 3H), 1.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.7, 136.6, 135.3, 133.0, 131.2, 130.7, 128.4, 128.0, 125.5, 124.3, 118.78, 118.75, 116.9, 95.4, 75.5, 9.3, 4.2; IR (KBr) 3053, 3032, 2917, 2860, 2228, 1656, 1617, 1597, 1495, 1474, 1455, 1393, 1355, 1323, 1254, 1216, 1205, 1176, 1156, 1073, 1030, 871, 852, 748, 727, 700, 538 cm–1; LRMS-ESI (m/z): 274.18 [M + H]+; HRMS (TOF-ES) (m/z): 274.1232 [M + H]+ calcd for C19H16NO, found 274.1233.

(3-Methyl-2-phenyl-1H-indol-1-yl)(phenyl)methanone (6aaf)

Chromatography purification (0–10% EtOAc in hexanes) gave 74 mg, 32%; pale yellow solid; mp 114–116 °C; 1H NMR (400 MHz, CDCl3) δ 7.70–7.66 (m, 1H), 7.63–7.60 (m, 1H), 7.59–7.55 (m, 2H), 7.40–7.34 (m, 1H), 7.31 (qd, J = 7.2, 1.4 Hz, 2H), 7.27–7.17 (m, 6H), 7.16–7.09 (m, 1H), 2.32 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.0, 137.3, 136.5, 135.8, 132.8, 132.4, 130.7, 130.1, 130.0, 128.2, 128.1, 127.4, 124.6, 123.0, 119.1, 116.8, 114.3, 9.6; IR (KBr) 3062, 3030, 2917, 2860, 1675, 1600, 1578, 1493, 1426, 1452, 1393, 1351, 1330, 1223, 1188, 1174, 1150, 1051, 1025, 883, 856, 843, 787, 762, 754, 747, 721, 696, 662, 527, 491 cm–1; LRMS-ESI (m/z): 312.33 [M + H]+; HRMS (TOF-ES) (m/z): 312.1388 [M + H]+ calcd for C22H18NO, found 312.1386.

(2-Iodophenyl)(3-methyl-2-phenyl-1H-indol-1-yl)methanone (6aag)

Chromatography purification (0–10% EtOAc in hexanes) gave 140 mg, 43%; colorless gum; 1H NMR (400 MHz, CDCl3) δ 8.20–8.10 (m, 1H), 7.63–7.53 (m, 2H), 7.44–7.33 (m, 2H), 7.22–7.12 (m, 4H), 7.11–7.03 (m, 3H), 6.82 (ddd, J = 8.0, 6.0, 3.2 Hz, 1H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.5, 141.5, 139.6, 137.2, 135.5, 132.4, 131.3, 130.9, 130.5, 130.3, 127.9, 127.6, 127.5, 125.4, 123.9, 119.0, 118.8, 115.6, 94.5, 9.4; IR (KBr) 3054, 1682, 1494, 1454, 1427, 1354, 1321, 1221, 1183, 1060, 1032, 1016, 885, 749, 700, 673, 638, 530 cm–1; LRMS-ESI (m/z): 438.06 [M + H]+; HRMS (TOF-ES) (m/z): 438.0355 [M + H]+ calcd for C22H17INO, found 438.0358.

(2-Chlorophenyl)(3-methyl-2-phenyl-1H-indol-1-yl)methanone (6aah)

Chromatography purification (0–10% EtOAc in hexanes) gave 105 mg, 41%; white solid; mp 90–92 °C; 1H NMR (400 MHz, CDCl3) δ 8.23–8.17 (m, 1H), 7.62–7.55 (m, 1H), 7.43–7.34 (m, 2H), 7.19–7.11 (m, 5H), 7.11–7.04 (m, 3H), 7.01 (ddd, J = 7.5, 6.7, 1.9 Hz, 1H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 167.4, 136.9, 136.2, 135.6, 132.2, 132.1, 131.4, 131.0, 130.4, 130.2, 129.8, 127.8, 127.6, 126.4, 125.4, 123.9, 119.0, 118.5, 115.5, 9.4; IR (KBr) 3055, 3029, 2912, 2859, 1687, 1592, 1494, 1474, 1454, 1441, 1437, 1392, 1355, 1327, 1222, 1187, 1158, 1122, 1068, 1042, 1030, 887, 767, 762, 752, 739, 730, 700, 647, 490, 474 cm–1; LRMS-ESI (m/z): 346.12 [M + H]+; HRMS (TOF-ES) (m/z): 346.0999 [M + H]+ calcd for C22H17ClNO, found 346.1000.

1-(3-Methyl-2-phenyl-1H-indol-1-yl)ethan-1-one (6aai)

Chromatography purification (0–10% EtOAc in hexanes) gave 44 mg, 24%; white solid; mp 80–82 °C; 1H NMR (400 MHz, CDCl3) δ 8.45–8.40 (m, 1H), 7.53 (ddd, J = 7.5, 1.5, 0.7 Hz, 1H), 7.52–7.47 (m, 2H), 7.47–7.42 (m, 1H), 7.42–7.36 (m, 3H), 7.33 (td, J = 7.4, 1.2 Hz, 1H), 2.15 (s, 3H), 1.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.2, 136.9, 135.1, 133.8, 130.4, 128.9, 128.6, 125.5, 123.6, 118.7, 118.3, 116.5, 27.8, 9.4; IR (KBr) 3055, 3028, 2918, 2860, 1697, 1450, 1392, 1364, 1348, 1315, 1304, 1198, 1165, 1155, 1072, 1023, 936, 921, 799, 750, 705, 670, 655, 610, 570, 559 cm–1; LRMS-ESI (m/z): 250.09 [M + H]+; HRMS (TOF-ES) (m/z): 250.1232 [M + H]+ calcd for C17H16NO, found 250.1234.

1-(2,3-Diphenyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6baa)

Chromatography purification (0–10% EtOAc in hexanes) gave 250 mg, 85%; yellow solid; mp 141–143 °C; 1H NMR (400 MHz, CDCl3) δ 8.60 (dt, J = 8.3, 1.0 Hz, 1H), 7.59 (dt, J = 7.8, 1.0 Hz, 1H), 7.49–7.40 (m, 3H), 7.38–7.26 (m, 8H), 7.26–7.21 (m, 4H), 7.11–7.05 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 152.3, 136.8, 135.3, 133.1, 132.9, 132.0, 131.7, 130.6, 130.2, 129.9, 128.7, 128.5, 128.4, 128.2, 127.2, 125.9, 124.7, 124.2, 119.9, 119.7, 116.7, 97.2, 83.6; IR (KBr) 3047, 2215, 1653, 1607, 1601, 1573, 1489, 1453, 1442, 1383, 1353, 1329, 1312, 1235, 1158, 1153, 1124, 1103, 1072, 1029, 983, 940, 936, 842, 824, 781, 757, 753, 737, 706, 698, 693, 689, 614, 591, 529 cm–1; LRMS-ESI (m/z): 420.15 [M + Na]+; HRMS (TOF-ES) (m/z): 398.1545 [M + H]+ calcd for C29H20NO, found 398.1548.

3-Phenyl-1-(3-phenyl-2-(m-tolyl)-1H-indol-1-yl)prop-2-yn-1-one (6bca)

Chromatography purification (0–10% EtOAc in hexanes) gave 257 mg, 84%; yellow solid; mp 49–51 °C; 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.3 Hz, 1H), 7.62–7.57 (m, 1H), 7.48–7.43 (m, 1H), 7.38–7.32 (m, 3H), 7.32–7.29 (m, 2H), 7.28–7.25 (m, 4H), 7.25–7.21 (m, 3H), 7.19 (d, J = 7.5 Hz, 1H), 7.12–7.04 (m, 3H), 2.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.3, 137.7, 136.8, 135.5, 133.0, 132.9, 132.3, 131.8, 130.5, 130.2, 130.1, 129.9, 129.5, 128.8, 128.4, 128.3, 128.19, 128.17, 128.1, 127.1, 126.8, 125.8, 124.7, 123.9, 119.8, 116.7, 96.9, 83.6, 21.4; IR (KBr) 3051, 3032, 2951, 2920, 2859, 2202, 1657, 1604, 1490, 1454, 1443, 1381, 1351, 1323, 1220, 1157, 1102, 1032, 1025, 940, 824, 777, 754, 743, 700, 689, 616, 535 cm–1; LRMS-ESI (m/z): 412.30 [M + H]+; HRMS (TOF-ES) (m/z): 412.1701 [M + H]+ calcd for C30H22NO, found 412.1706.

3-Phenyl-1-(3-phenyl-2-(p-tolyl)-1H-indol-1-yl)prop-2-yn-1-one (6bda)

Chromatography purification (0–10% EtOAc in hexanes) gave 257 mg, 84%; yellow solid; mp 153–155 °C; 1H NMR (400 MHz, CDCl3) δ 8.60 (dt, J = 8.3, 0.9 Hz, 1H), 7.58 (dt, J = 7.7, 1.0 Hz, 1H), 7.44 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.38–7.21 (m, 11H), 7.12–7.03 (m, 4H), 2.24 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.3, 138.7, 136.8, 135.5, 133.1, 132.9, 131.7, 130.4, 130.2, 129.9, 129.0, 128.9, 128.4, 128.2, 127.1, 125.7, 124.7, 123.8, 120.0, 119.8, 116.9, 97.0, 83.5, 21.4; IR (KBr) 3050, 3031, 2922, 2211, 1654, 1622, 1608, 1490, 1452, 1444, 1384, 1354, 1323, 1217, 1158, 1099, 1024, 984, 839, 768, 759, 751, 743, 703, 690, 631, 613, 532 cm–1; LRMS-ESI (m/z): 412.36 [M + H]+; HRMS (TOF-ES) (m/z): 412.1701 [M + H]+ calcd for C30H22NO, found 412.1703.

1-(2-(3-Fluorophenyl)-3-phenyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6bia)

Chromatography purification (0–10% EtOAc in hexanes) gave 225 mg, 73%; yellow solid; mp 131–133 °C; 1H NMR (400 MHz, CDCl3) δ 8.58 (dt, J = 8.3, 0.9 Hz, 1H), 7.58 (dt, J = 7.8, 1.0 Hz, 1H), 7.47 (ddd, J = 8.4, 7.2, 1.4 Hz, 1H), 7.40–7.30 (m, 5H), 7.30–7.26 (m, 2H), 7.26–7.21 (m, 4H), 7.18–7.12 (m, 3H), 6.97–6.90 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.4 (d, JC–F = 246.7 Hz), 151.9, 136.8, 134.3 (d, JC–F = 8.4 Hz), 133.7 (d, JC–F = 2.3 Hz), 132.8, 132.5, 130.7, 130.1, 129.8, 129.7, 128.5, 128.4, 127.6 (d, JC–F = 3.0 Hz), 127.5, 126.2, 124.9, 124.8, 120.1, 119.6, 118.5 (d, JC–F = 22.2 Hz), 116.7, 115.7 (d, JC–F = 21.1 Hz), 96.9, 83.6; IR (KBr) 3047, 2212, 1655, 1588, 1575, 1490, 1485, 1381, 1351, 1328, 1196, 1160, 1149, 1113, 1102, 1072, 1031, 1024, 993, 940, 915, 880, 757, 745, 706, 703, 686, 616, 523 cm–1; LRMS-ESI (m/z): 416.36 [M + H]+; HRMS (TOF-ES) (m/z): 416.1451 [M + H]+ calcd for C29H19FNO, found 416.1452.

1-(2-(4-Fluorophenyl)-3-phenyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6bja)

Chromatography purification (0–10% EtOAc in hexanes) gave 212 mg, 69%; yellow solid; mp 120–122 °C; 1H NMR (400 MHz, CDCl3) δ 8.60 (dt, J = 8.4, 0.9 Hz, 1H), 7.58 (dt, J = 7.8, 1.0 Hz, 1H), 7.49–7.37 (m, 4H), 7.37–7.32 (m, 2H), 7.32–7.29 (m, 2H), 7.29–7.21 (m, 4H), 7.17–7.11 (m, 2H), 7.04–6.97 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 163.0 (d, JC–F = 249.1 Hz), 152.0, 136.7, 134.1, 133.6 (d, JC–F = 8.2 Hz), 132.7, 132.69, 130.7, 130.1, 129.7, 128.5, 128.4, 128.1 (d, JC–F = 3.5 Hz), 127.4, 126.0, 124.8, 124.5, 119.9, 119.6, 116.8, 115.4 (d, JC–F = 21.7 Hz), 97.3, 83.5; IR (KBr) 3065, 2199, 1683, 1655, 1602, 1594, 1572, 1511, 1489, 1454, 1443, 1387, 1363, 1332, 1232, 1219, 1123, 1103, 1032, 1016, 988, 938, 923, 852, 800, 768, 763, 758, 745, 703, 694, 688, 615, 536 cm–1; LRMS-ESI (m/z): 416.17 [M + H]+; HRMS (TOF-ES) (m/z): 416.1451 [M + H]+ calcd for C29H19FNO, found 416.1449.

1-(2-(4-(tert-Butyl)phenyl)-3-phenyl-1H-indol-1-yl)-3-phenylprop-2-yn-1-one (6bva)

Chromatography purification (0–10% EtOAc in hexanes) gave 302 mg, 90%; yellow solid; mp 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 8.58 (dt, J = 8.2, 0.9 Hz, 1H), 7.58 (ddd, J = 7.8, 1.3, 0.7 Hz, 1H), 7.44 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.39–7.33 (m, 3H), 7.33–7.27 (m, 6H), 7.26–7.18 (m, 4H), 7.09–7.04 (m, 2H), 1.16 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 152.4, 151.4, 136.8, 135.5, 133.1, 132.9, 131.3, 130.5, 130.2, 129.9, 128.9, 128.3, 128.2, 127.1, 125.7, 125.2, 124.7, 123.8, 119.9, 119.8, 116.7, 96.8, 83.6, 34.7, 31.2; IR (KBr) 3064, 2969, 2905, 2870, 2199, 1654, 1602, 1594, 1489, 1452, 1443, 1385, 1346, 1322, 1266, 1216, 1156, 1128, 1098, 1071, 1032, 1021, 985, 939, 925, 852, 844, 759, 749, 736, 702, 688, 628, 612, 538 cm–1; LRMS-ESI (m/z): 476.25 [M + Na]+; HRMS (TOF-ES) (m/z): 454.2171 [M + H]+ calcd for C33H28NO, found 454.2172.

3-Phenyl-1-(3-phenyl-2-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)prop-2-yn-1-one (6bwa)

Chromatography purification (0–10% EtOAc in hexanes) gave 98 mg, 29%; yellow solid; mp 133–135 °C; 1H NMR (400 MHz, CDCl3) δ 8.61 (dd, J = 8.3, 0.9 Hz, 1H), 7.60–7.53 (m, 5H), 7.48 (ddd, J = 8.5, 7.2, 1.3 Hz, 1H), 7.40–7.29 (m, 5H), 7.26–7.18 (m, 4H), 7.06–6.97 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 151.8, 137.0, 136.0, 133.5, 132.6, 132.3, 132.0, 130.9, 130.7 (q, JC–F = 32.7 Hz), 130.1, 129.8, 128.7, 128.4, 127.6, 126.4, 125.5, 125.1 (q, JC–F = 3.7 Hz), 125.0, 124.0 (q, JC–F = 272.4 Hz), 120.2, 119.2, 116.8, 97.4, 83.6; IR (KBr) 3060, 2194, 1655, 1620, 1605, 1490, 1453, 1444, 1406, 1386, 1356, 1326, 1181, 1171, 1158, 1125, 1107, 1066, 1018, 984, 938, 855, 811, 778, 753, 731, 753, 699, 687, 617, 534 cm–1; LRMS-ESI (m/z): 466.29 [M + H]+; HRMS (TOF-ES) (m/z): 466.1419 [M + H]+ calcd for C30H19F3NO, found 466.1422.

Typical Procedure for the Synthesis of Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-phenylacetate (7aaa)

To a stirred solution of 2′-aminoacetophenone (100 mg, 0.740 mmol) and benzaldehyde (118 mg, 1.112 mmol) in MeOH (2.0 mL) was added 3-phenylpropiolic acid (119 mg, 0.814 mmol) at room temperature. After 30 min stirring, cyclohexylisocyanide (0.101 mL, 0.814 mmol) was added, and the resulting reaction mixture was stirred for 16 h. TLC showed the formation of Ugi product. Then, the reaction mixture was diluted with MeOH (47.0 mL, 0.015 M) and CSA (429 mg, 1.850 mmol) was added and heated to 120 °C for 96 h. After completion of the reaction, the reaction mixture was concentrated and dried well. The crude was purified by silica gel (230–400 mesh) column chromatography (0–40% EtOAc in hexanes) to afford 7aaa, 228 mg, 75%; pale yellow solid; mp 208–210 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.3 Hz, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.50–7.44 (m, 3H), 7.42 (d, J = 7.4 Hz, 2H), 7.36–7.27 (m, 4H), 7.23 (d, J = 8.6 Hz, 1H), 6.88 (s, 1H), 3.70 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.2, 169.0, 160.0, 145.4, 138.5, 136.8, 134.0, 133.6, 131.2, 130.7, 129.4, 128.9, 128.6, 128.3, 128.2, 126.2, 123.0, 121.5, 115.8, 58.9, 52.9, 16.3; IR (KBr) 3062, 3033, 3005, 2951, 2925, 2844, 1751, 1675, 1638, 1596, 1568, 1498, 1455, 1435, 1387, 1373, 1318, 1266, 1209, 1170, 1025, 1007, 890, 821, 752, 737, 697, 664 cm–1; LRMS-ESI (m/z): 434.43 [M + Na]+; HRMS (TOF-ES) (m/z): 412.1549 [M + H]+ calcd for C26H22NO4, found 412.1549.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(o-tolyl)acetate (7aba)

Chromatography purification (0–40% EtOAc in hexanes) gave 264 mg, 84%; off-white solid; mp 221–223 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 2H), 7.85 (d, J = 7.4 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.51–7.43 (m, 3H), 7.30 (t, J = 7.6 Hz, 1H), 7.24–7.19 (m, 2H), 7.16–7.06 (m, 3H), 6.56 (s, 1H), 3.68 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.2, 168.3, 160.1, 145.3, 139.0, 136.82, 136.81, 133.9, 131.9, 131.3, 130.9, 130.87, 129.5, 128.9, 128.5, 127.2, 126.5, 126.1, 123.1, 121.6, 115.4, 58.9, 52.9, 19.6, 16.3; IR (KBr) 3080, 3060, 3028, 2997, 2951, 2926, 1751, 1675, 1638, 1597, 1568, 1498, 1456, 1450, 1387, 1318, 1266, 1205, 1169, 1002, 896, 822, 747, 740, 689, 664 cm–1; LRMS-ESI (m/z): 448.47 [M + Na]+; HRMS (TOF-ES) (m/z): 426.1705 [M + H]+ calcd for C27H24NO4, found 426.1707.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(m-tolyl)acetate (7aca)

Chromatography purification (0–40% EtOAc in hexanes) gave 216 mg, 69%; white solid; mp 240–242 °C; 1H NMR (400 MHz, CDCl3) δ 8.00–7.92 (m, 2H), 7.84 (dd, J = 8.1, 1.6 Hz, 1H), 7.64–7.55 (m, 1H), 7.53–7.42 (m, 3H), 7.33–7.26 (m, 2H), 7.25–7.18 (m, 3H), 7.15–7.07 (m, 1H), 6.78 (s, 1H), 3.69 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.3, 169.0, 160.0, 145.4, 138.6, 138.4, 136.8, 133.9, 133.7, 131.2, 130.7, 129.4, 129.1, 128.9, 128.86, 128.5, 126.1, 125.3, 123.0, 121.5, 115.8, 59.1, 52.9, 21.7, 16.3; IR (KBr) 3084, 3060, 3031, 3003, 2951, 2923, 1751, 1674, 1635, 1596, 1569, 1498, 1456, 1449, 1387, 1372, 1318, 1266, 1204, 1171, 1026, 822, 780, 757, 698, 664 cm–1; LRMS-ESI (m/z): 448.28 [M + Na]+; HRMS (TOF-ES) (m/z): 426.1705 [M + H]+ calcd for C27H24NO4, found 426.1708.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(p-tolyl)acetate (7ada)

Chromatography purification (0–40% EtOAc in hexanes) gave 231 mg, 73%; white solid; mp 195–197 °C; 1H NMR (400 MHz, CDCl3) δ 7.99–7.91 (m, 2H), 7.84 (dd, J = 8.1, 1.6 Hz, 1H), 7.63–7.55 (m, 1H), 7.52–7.44 (m, 3H), 7.31 (d, J = 7.6 Hz, 2H), 7.29–7.22 (m, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.80 (s, 1H), 3.69 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.3, 169.2, 160.0, 145.3, 138.6, 138.1, 136.8, 134.0, 131.2, 130.7, 130.69, 129.5, 129.4, 128.9, 128.2, 126.1, 123.0, 121.5, 115.8, 58.9, 52.9, 21.2, 16.3; IR (KBr) 3082, 3059, 3029, 3005, 2951, 2922, 1752, 1676, 1673, 1638, 1596, 1568, 1516, 1499, 1456, 1449, 1435, 1387, 1318, 1266, 1207, 1170, 1113, 1024, 1003, 894, 822, 782, 760, 738, 688, 664 cm–1; LRMS-ESI (m/z): 448.42 [M + Na]+; HRMS (TOF-ES) (m/z): 426.1705 [M + H]+ calcd for C27H24NO4, found 426.1707.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(2-methoxyphenyl)acetate (7aea)

Chromatography purification (0–40% EtOAc in hexanes) gave 294 mg, 90%; white solid; mp 231–233 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 1H), 7.34–7.27 (m, 3H), 6.95 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.67 (s, 1H), 3.95 (s, 3H), 3.64 (s, 3H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.3, 168.3, 160.2, 157.1, 145.2, 139.2, 136.8, 133.9, 131.5, 131.1, 129.9, 129.5, 129.1, 128.8, 126.0, 122.9, 122.7, 121.5, 121.2, 115.1, 110.6, 55.9, 55.4, 52.7, 16.2; IR (KBr) 3081, 3057, 3000, 2950, 2840, 1752, 1676, 1638, 1597, 1568, 1492, 1457, 1449, 1388, 1319, 1250, 1207, 1170, 1104, 1026, 1003, 959, 896, 822, 781, 754, 713, 689, 664 cm–1; LRMS-ESI (m/z): 464.49 [M + Na]+; HRMS (TOF-ES) (m/z): 442.1654 [M + H]+ calcd for C27H24NO5, found 442.1655.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(3-methoxyphenyl)acetate (7afa)

Chromatography purification (0–40% EtOAc in hexanes) gave 223 mg, 68%; pale yellow solid; mp 200–202 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.7 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.52–7.42 (m, 3H), 7.34–7.19 (m, 3H), 7.03 (s, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.87–6.79 (m, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.2, 168.9, 160.0, 159.8, 145.5, 138.6, 136.8, 135.3, 134.0, 131.2, 130.7, 129.7, 129.5, 128.9, 126.2, 123.0, 121.5, 120.6, 115.9, 114.3, 113.6, 58.9, 55.4, 53.0, 16.3; IR (KBr) 3082, 3060, 2999, 2951, 2835, 1750, 1674, 1637, 1596, 1568, 1493, 1456, 1450, 1435, 1387, 1372, 1317, 1266, 1206, 1171, 1045, 1009, 959, 891, 822, 780, 758, 696, 664 cm–1; LRMS-ESI (m/z): 464.49 [M + Na]+; HRMS (TOF-ES) (m/z): 442.1654 [M + H]+ calcd for C27H24NO5, found 442.1659.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-methoxyphenyl)acetate (7aga)

Chromatography purification (0–40% EtOAc in hexanes) gave 259 mg, 79%; off-white solid; mp 172–174 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.5 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.51–7.44 (m, 3H), 7.37 (d, J = 8.5 Hz, 2H), 7.32–7.26 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.76 (s, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.3, 169.2, 160.0, 159.4, 145.3, 138.6, 136.8, 134.0, 131.2, 130.7, 129.7, 129.5, 128.9, 126.2, 125.8, 123.0, 121.5, 115.7, 114.1, 58.7, 55.4, 52.9, 16.3; IR (KBr) 3081, 3059, 3002, 2952, 2932, 2838, 1751, 1674, 1637, 1614, 1569, 1515, 1500, 1456, 1450, 1387, 1318, 1254, 1211, 1180, 1113, 1030, 1003, 894, 822, 782, 754, 738, 688, 664 cm–1; LRMS-ESI (m/z): 464.52 [M + Na]+; HRMS (TOF-ES) (m/z): 442.1654 [M + H]+ calcd for C27H24NO5, found 442.1656.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(2-fluorophenyl)acetate (7aha)

Chromatography purification (0–40% EtOAc in hexanes) gave 285 mg, 90%; white solid; mp 199–201 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.7 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.64–7.54 (m, 2H), 7.50–7.44 (m, 2H), 7.44–7.39 (m, 1H), 7.39–7.28 (m, 3H), 7.17–7.09 (m, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.60 (s, 1H), 3.67 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 167.6, 160.9 (d, JC–F = 246.5 Hz) 160.2, 145.6, 138.8, 136.7, 134.0, 131.7, 131.0, 130.5 (d, JC–F = 8.5 Hz), 130.0 (d, JC–F = 2.7 Hz), 129.5, 128.9, 126.3, 124.8 (d, JC–F = 3.4 Hz), 123.3, 121.7, 121.6, 115.4 (d, JC–F = 21.8 Hz), 114.6 (d, JC–F = 2.3 Hz), 54.7 (d, JC–F = 3.5 Hz), 53.1, 16.3; IR (KBr) 3085, 3059, 3003, 2952, 2922, 2845, 1755, 1675, 1640, 1597, 1569, 1490, 1457, 1451, 1387, 1318, 1266, 1229, 1211, 1171, 1095, 1003, 897, 823, 754, 688, 664 cm–1; LRMS-ESI (m/z): 452.40 [M + Na]+; HRMS (TOF-ES) (m/z): 430.1455 [M + H]+ calcd for C26H21FNO4, found 430.1454.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(3-fluorophenyl)acetate (7aia)

Chromatography purification (0–40% EtOAc in hexanes) gave 306 mg, 96%; off-white solid; mp 213–215 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.1 Hz, 2H), 7.86 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.53–7.43 (m, 3H), 7.35–7.27 (m, 2H), 7.22–7.14 (m, 3H), 7.04–6.96 (m, 1H), 6.84 (s, 1H), 3.70 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 168.6, 162.9 (d, JC–F = 246.2 Hz), 160.0, 145.7, 138.4, 136.8, 136.1 (d, JC–F = 7.5 Hz), 134.0, 131.4, 130.6, 130.2 (d, JC–F = 8.2 Hz), 129.4, 128.9, 126.4, 123.9 (d, JC–F = 2.9 Hz), 123.2, 121.6, 115.6 (d, JC–F = 23.1 Hz), 115.4 (d, JC–F = 33.6 Hz), 58.3, 53.1, 16.4; IR (KBr) 3083, 3064, 3030, 3000, 2952, 2923, 2846, 1752, 1674, 1638, 1595, 1569, 1490, 1456, 1450, 1387, 1318, 1268, 1247, 1207, 1172, 1025, 936, 891, 822, 781, 760, 695, 664 cm–1; LRMS-ESI (m/z): 452.43 [M + Na]+; HRMS (TOF-ES) (m/z): 430.1455 [M + H]+ calcd for C26H21FNO4, found 430.1454.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-fluorophenyl)acetate (7aja)

Chromatography purification (0–40% EtOAc in hexanes) gave 220 mg, 69%; off-white solid; mp 170–172 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 7.2, 1.9 Hz, 2H), 7.86 (dd, J = 8.0, 1.9 Hz, 1H), 7.64–7.56 (m, 1H), 7.54–7.37 (m, 5H), 7.32 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.01 (td, J = 8.6, 1.9 Hz, 2H), 6.74 (s, 1H), 3.68 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 168.9, 162.5 (d, JC–F = 247.4 Hz), 159.9, 145.5, 138.5, 136.7, 134.0, 131.4, 130.7, 130.3 (d, JC–F = 8.3 Hz), 129.5, 129.49, 128.9, 126.3, 123.2, 121.6, 115.6 (d, JC–F = 21.6 Hz), 115.4, 58.5, 53.0, 16.3; IR (KBr) 3082, 3063, 3002, 2952, 2925, 2851, 1752, 1673, 1637, 1596, 1569, 1511, 1456, 1450, 1388, 1318, 1266, 1212, 1162, 1004, 894, 822, 754, 688, 664 cm–1; LRMS-ESI (m/z): 452.56 [M + Na]+; HRMS (TOF-ES) (m/z): 430.1455 [M + H]+ calcd for C26H21FNO4, found 430.1456.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(2-chlorophenyl)acetate (7aka)

Chromatography purification (0–40% EtOAc in hexanes) gave 284 mg, 86%; off-white solid; mp 190–192 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.5 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.64–7.53 (m, 2H), 7.51–7.43 (m, 3H), 7.38–7.31 (m, 2H), 7.30–7.27 (m, 1H), 7.23–7.14 (m, 2H), 6.49 (s, 1H), 3.65 (s, 3H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 167.1, 160.2, 145.7, 139.0, 136.7, 134.1, 134.0, 131.9, 131.8, 131.1, 130.0, 129.6, 129.56, 129.3, 128.9, 127.7, 126.3, 123.4, 121.6, 114.6, 59.2, 53.0, 16.3; IR (KBr) 3062, 3029, 2999, 2951, 2841, 1754, 1675, 1639, 1597, 1569, 1499, 1473, 1456, 1448, 1387, 1374, 1318, 1266, 1209, 1170, 1042, 1002, 897, 821, 780, 751, 708, 687, 663 cm–1; LRMS-ESI (m/z): 468.64 [M + Na]+; HRMS (TOF-ES) (m/z): 446.1159 [M + H]+ calcd for C26H21ClNO4, found 446.1159.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(3-chlorophenyl)acetate (7ala)

Chromatography purification (0–40% EtOAc in hexanes) gave 215 mg, 65%; off-white solid; mp 211–213 °C; 1H NMR (400 MHz, CDCl3) δ 7.98–7.91 (m, 2H), 7.87 (dd, J = 8.1, 1.5 Hz, 1H), 7.64–7.57 (m, 1H), 7.55–7.43 (m, 5H), 7.36–7.29 (m, 2H), 7.17 (d, J = 8.6 Hz, 1H), 7.00 (s, 1H), 6.76 (s, 1H), 3.69 (s, 3H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 168.5, 160.0, 145.7, 138.4, 136.8, 135.7, 134.7, 134.0, 131.5, 130.7, 130.0, 129.5, 129.0, 128.6, 128.5, 126.5, 126.4, 123.2, 121.6, 115.5, 58.5, 53.1, 16.4; IR (KBr) 3063, 3028, 2999, 2951, 2927, 2892, 1750, 1674, 1637, 1596, 1569, 1499, 1456, 1450, 1434, 1387, 1372, 1318, 1268, 1211, 1171, 1025, 1008, 822, 756, 694, 664 cm–1; LRMS-ESI (m/z): 468.69 [M + Na]+; HRMS (TOF-ES) (m/z): 446.1159 [M + H]+ calcd for C26H21ClNO4, found 446.1159.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-chlorophenyl)acetate (7ama)

Chromatography purification (0–40% EtOAc in hexanes) gave 227 mg, 69%; off-white solid; mp 203–205 °C; 1H NMR (400 MHz, CDCl3) δ 7.97–7.92 (m, 2H), 7.86 (dd, J = 8.1, 1.5 Hz, 1H), 7.64–7.56 (m, 1H), 7.53–7.44 (m, 3H), 7.40–7.35 (m, 2H), 7.35–7.28 (m, 3H), 7.17 (d, J = 8.5 Hz, 1H), 6.77 (s, 1H), 3.69 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 168.7, 159.9, 145.6, 138.4, 136.7, 134.3, 134.1, 132.2, 131.4, 130.7, 129.8, 129.5, 128.9, 128.86, 126.4, 123.2, 121.6, 115.4, 58.4, 53.1, 16.3; IR (KBr) 3086, 3058, 3000, 2951, 2927, 1751, 1674, 1637, 1596, 1569, 1494, 1457, 1449, 1387, 1373, 1318, 1267, 1212, 1171, 1092, 1016, 1005, 895, 848, 764, 754, 685, 664 cm–1; LRMS-ESI (m/z): 468.56 [M + Na]+; HRMS (TOF-ES) (m/z): 446.1159 [M + H]+ calcd for C26H21ClNO4, found 446.1158.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(2-bromophenyl)acetate (7ana)

Chromatography purification (0–40% EtOAc in hexanes) gave 285 mg, 79%; white solid; mp 192–194 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 7.2, 1.7 Hz, 2H), 7.86 (dd, J = 8.1, 1.5 Hz, 1H), 7.65 (dd, J = 7.3, 1.9 Hz, 1H), 7.62–7.54 (m, 2H), 7.51–7.43 (m, 2H), 7.37–7.29 (m, 2H), 7.25–7.15 (m, 3H), 6.41 (s, 1H), 3.65 (s, 3H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.0, 167.0, 160.2, 145.7, 139.0, 136.7, 134.0, 133.4, 132.9, 131.9, 131.1, 130.2, 129.5, 129.4, 128.8, 128.3, 126.3, 124.6, 123.4, 121.6, 114.7, 61.9, 53.0, 16.3; IR (KBr) 3063, 3031, 2996, 2951, 2928, 2849, 1754, 1675, 1640, 1597, 1569, 1499, 1470, 1456, 1449, 1387, 1373, 1318, 1266, 1208, 1170, 1030, 1002, 897, 821, 780, 750, 707, 689, 663 cm–1; LRMS-ESI (m/z): 512.69 [M + Na]+; HRMS (TOF-ES) (m/z): 490.0654 [M + H]+ calcd for C26H21BrNO4, found 490.0656.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(3-bromophenyl)acetate (7aoa)

Chromatography purification (0–40% EtOAc in hexanes) gave 231 mg, 64%; pale yellow solid; mp 208–210 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.63–7.56 (m, 2H), 7.54–7.41 (m, 4H), 7.37–7.29 (m, 2H), 7.23–7.14 (m, 2H), 6.74 (s, 1H), 3.69 (s, 3H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 168.4, 159.9, 145.8, 138.3, 136.7, 135.9, 134.0, 131.5, 131.49, 131.3, 130.6, 130.2, 129.4, 128.9, 127.0, 126.4, 123.3, 122.7, 121.5, 115.3, 58.4, 53.1, 16.4; IR (KBr) 3085, 3064, 3000, 2951, 2839, 1750, 1673, 1637, 1596, 1568, 1499, 1456, 1449, 1387, 1318, 1267, 1210, 1170, 1007, 897, 821, 757, 697, 687, 664 cm–1; LRMS-ESI (m/z): 490.26 [M + H]+; HRMS (TOF-ES) (m/z): 490.0654 [M + H]+ calcd for C26H21BrNO4, found 490.0659.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-bromophenyl)acetate (7apa)

Chromatography purification (0–40% EtOAc in hexanes) gave 212 mg, 58%; pale yellow solid; mp 206–208 °C; 1H NMR (400 MHz, CDCl3) δ 7.97–7.91 (m, 2H), 7.86 (dd, J = 8.1, 1.5 Hz, 1H), 7.64–7.56 (m, 1H), 7.54–7.41 (m, 5H), 7.36–7.28 (m, 3H), 7.16 (d, J = 8.6 Hz, 1H), 6.75 (s, 1H), 3.68 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.1, 168.6, 159.9, 145.6, 138.4, 136.7, 134.1, 132.7, 131.8, 131.4, 130.7, 130.1, 129.5, 128.9, 126.4, 123.2, 122.5, 121.6, 115.4, 58.5, 53.1, 16.4; IR (KBr) 3084, 3061, 3031, 2998, 2950, 1751, 1674, 1636, 1596, 1569, 1498, 1489, 1456, 1449, 1387, 1372, 1318, 1266, 1211, 1171, 1074, 1006, 895, 847, 820, 754, 689, 663 cm–1; LRMS-ESI (m/z): 512.60 [M + Na]+; HRMS (TOF-ES) (m/z): 490.0654 [M + H]+ calcd for C26H21BrNO4, found 490.0654.

Methyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(4-(tert-butyl)phenyl)acetate (7ava)

Chromatography purification (0–40% EtOAc in hexanes) gave 253 mg, 73%; yellow solid; mp 233–235 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.4 Hz, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.52–7.43 (m, 3H), 7.39–7.27 (m, 6H), 6.86 (s, 1H), 3.69 (s, 3H), 2.43 (s, 3H), 1.28 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 195.3, 169.3, 160.0, 151.1, 145.3, 138.7, 136.9, 133.9, 131.2, 130.8, 130.5, 129.5, 128.9, 128.0, 126.1, 125.6, 122.9, 121.5, 116.0, 58.6, 52.9, 34.6, 31.4, 16.3; IR (KBr) 3059, 3033, 2962, 2931, 2905, 2867, 1751, 1675, 1639, 1596, 1568, 1514, 1500, 1456, 1449, 1387, 1318, 1267, 1214, 1170, 1112, 1024, 1002, 959, 894, 820, 754, 687, 664 cm–1; LRMS-ESI (m/z): 490.84 [M + Na]+; HRMS (TOF-ES) (m/z): 468.2175 [M + H]+ calcd for C30H30NO4, found 468.2176.

Methyl 2-(3-(4-methoxybenzoyl)-4-methyl-2-oxoquinolin-1(2H)-yl)-2-(2-methoxyphenyl)acetate (7aec)

Chromatography purification (0–70% EtOAc in hexanes) gave 328 mg, 94%; white solid; mp 111–113 °C; 1H NMR (400 MHz, CDCl3) δ 7.96–7.89 (m, 2H), 7.81 (dd, J = 8.1, 1.5 Hz, 1H), 7.51 (ddd, J = 8.6, 7.1, 1.5 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.34–7.26 (m, 3H), 6.98–6.91 (m, 3H), 6.87 (td, J = 7.6, 1.1 Hz, 1H), 6.67 (s, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.66 (s, 3H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.7, 168.4, 164.3, 160.2, 157.1, 144.8, 139.1, 132.0, 131.4, 131.35, 131.25, 130.0, 129.8, 129.2, 126.0, 122.9, 122.8, 122.76, 121.6, 121.2, 115.1, 114.1, 113.9, 110.6, 55.9, 55.7, 55.5, 52.7, 16.3; IR (KBr) 3074, 3003, 2950, 2840, 1753, 1665, 1639, 1597, 1569, 1493, 1456, 1387, 1318, 1258, 1208, 1162, 1105, 1027, 845, 753, 663, 548 cm–1; LRMS-ESI (m/z): 494.32 [M + Na]+; HRMS (TOF-ES) (m/z): 472.1760 [M + H]+ calcd for C28H26NO6, found 472.1759.

N-(2-Acetylphenyl)-N-(2-(cyclohexylamino)-1-(2-methoxyphenyl)-2-oxoethyl)-3-(4-(trifluoromethyl)phenyl)propiolamide (7ead—Ugi Intermediate)

The recovery of Ugi intermediate purification was difficult because of contamination by unknown and inseparable impurities. Chromatography purification (0–40% EtOAc in hexanes) gave 255 mg, 60%; white solid; mp 167–169 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.55–7.49 (m, 1H), 7.45 (d, J = 7.7 Hz, 2H), 7.38–7.34 (m, 1H), 7.23–7.17 (m, 1H), 7.13 (d, J = 7.9 Hz, 2H), 6.88–6.83 (m, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 6.50 (s, 1H), 5.47 (d, J = 8.2 Hz, 1H), 3.86–3.78 (m, 1H), 3.70 (s, 3H), 2.24 (s, 3H), 2.00 (d, J = 12.4 Hz, 1H), 1.79 (d, J = 11.8 Hz, 1H), 1.73–1.64 (m, 2H), 1.42–1.27 (m, 3H), 1.21–1.06 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 198.4, 168.4, 167.2, 157.5, 157.4, 155.1, 139.2, 137.4, 134.1, 132.7, 132.4, 132.2, 131.9, 131.7, 130.7, 130.5, 130.1, 129.0, 128.9, 128.8, 128.6, 125.5, 125.43, 125.39, 125.36, 125.3, 125.28, 124.3, 120.8, 120.7, 120.4, 110.7, 110.6, 89.5, 84.8, 60.3, 57.7, 55.6, 55.1, 49.0, 48.6, 33.0, 32.9, 29.6, 29.5, 25.6, 25.0, 24.9; IR (KBr) 3309, 3072, 2932, 2855, 2223, 1685, 1642, 1596, 1495, 1404, 1356, 1323, 1250, 1169, 1129, 1107, 1067, 1017, 844, 755, 658, 598 cm–1; LRMS-ESI (m/z): 599.42 [M + Na]+; HRMS (TOF-ES) (m/z): 577.2314 [M + H]+ calcd for C33H32F3N2O4, found 577.2316.

2-((2-Acetylphenyl)amino)-N-cyclohexyl-2-(2-methoxyphenyl)acetamide (7aed—Amide Cleaved Byproduct)

Chromatography purification (0–25% EtOAc in hexanes) gave 5.6 mg, 2.0%; pale yellow solid; mp 125–127 °C; 1H NMR (400 MHz, CDCl3) δ 9.74 (d, J = 4.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.31–7.27 (m, 1H), 7.24 (s, 1H), 7.00–6.88 (m, 2H), 6.63 (t, J = 7.7 Hz, 1H), 6.55–6.43 (m, 2H), 5.32 (d, J = 5.7 Hz, 1H), 3.95 (s, 3H), 3.83–3.70 (m, 1H), 2.60 (s, 3H), 1.92 (d, J = 12.4 Hz, 1H), 1.78–1.61 (m, 2H), 1.54–1.48 (m, 1H), 1.44–1.23 (m, 3H), 1.21–1.09 (m, 2H), 1.06–0.90 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 200.8, 169.6, 156.6, 149.3, 135.0, 132.7, 129.3, 128.2, 127.0, 121.7, 118.9, 115.3, 112.9, 111.0, 56.6, 55.7, 48.1, 33.1, 32.8, 28.1, 25.6, 24.7, 24.6; IR (KBr) 3386, 3299, 3075, 2931, 2854, 1684, 1643, 1606, 1564, 1511, 1488, 1458, 1419, 1361, 1324, 1236, 1164, 1096, 1023, 953, 794, 752, 612, 519 cm–1; LRMS-ESI (m/z): 403.37 [M + Na]+; HRMS (TOF-ES) (m/z): 381.2181 [M + H]+ calcd for C23H29N2O3, found 381.2181.

Methyl 2-(2-fluorophenyl)-2-(3-(4-methoxybenzoyl)-4-methyl-2-oxoquinolin-1(2H)-yl)acetate (7ahc)

Chromatography purification (0–20% EtOAc in hexanes) gave 326 mg, 96%; white solid; mp 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.38–7.28 (m, 3H), 7.17–7.03 (m, 2H), 6.94 (d, J = 8.3 Hz, 2H), 6.61 (s, 1H), 3.87 (s, 3H), 3.69 (s, 3H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.5, 167.6, 164.3, 160.9 (d, JC–F = 246.6 Hz), 160.1, 145.2, 138.7, 132.0, 131.5, 131.2, 130.5 (d, JC–F = 8.5 Hz), 130.0, 129.9, 126.2, 124.7 (d, JC–F = 3.4 Hz), 123.2, 121.7 (d, JC–F = 12.5 Hz), 121.6, 115.3 (d, JC–F = 21.9 Hz), 114.6, 114.1, 55.7, 54.7, 53.0, 16.3; IR (KBr) 3071, 3052, 3006, 2953, 2904, 2842, 1754, 1666, 1640, 1598, 1571, 1510, 1490, 1457, 1387, 1317, 1260, 1231, 1213, 1179, 1163, 1028, 1009, 898, 846, 821, 754, 737, 663 cm–1; LRMS-ESI (m/z): 482.28 [M + Na]+; HRMS (TOF-ES) (m/z): 460.1560 [M + H]+ calcd for C27H23FNO5, found 460.1564.

N-(2-Acetylphenyl)-N-(2-(cyclohexylamino)-1-(2-fluorophenyl)-2-oxoethyl)-3-(4-(trifluoromethyl)phenyl)propiolamide (7ahd—Ugi Intermediate)

The recovery of Ugi intermediate purification was difficult because of contamination by unknown and inseparable impurities. Chromatography purification (0–40% EtOAc in hexanes) gave 193 mg, 46%; off-white solid; mp 98–100 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.8 Hz, 1H), 7.63–7.57 (m, 1H), 7.56–7.52 (m, 2H), 7.48–7.45 (m, 2H), 7.25–7.18 (m, 1H), 7.14–7.10 (m, 3H), 6.97 (d, J = 9.2 Hz, 1H), 6.88 (t, J = 7.7 Hz, 1H), 6.24 (s, 1H), 6.01 (d, J = 8.1 Hz, 1H), 3.88–3.74 (m, 1H), 2.24 (s, 3H), 2.04 (d, J = 12.2 Hz, 1H), 1.97–1.77 (m, 2H), 1.75–1.61 (m, 3H), 1.42–1.27 (m, 2H), 1.16–1.03 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 198.1, 167.4, 166.1, 162.2, 159.7, 154.8, 137.9, 137.4, 133.7, 132.7, 132.6, 132.2, 131.0, 131.95, 129.4, 129.3, 129.2, 128.9, 125.5, 125.47, 125.4, 125.38, 124.1, 122.3, 115.7, 115.5, 89.4, 84.5, 57.3, 49.2, 33.0, 32.8, 29.0, 25.6, 25.0, 24.9; IR (KBr) 3311, 3070, 2932, 2856, 2221, 1689, 1644, 1595, 1491, 1449, 1356, 1323, 1249, 1231, 1170, 1129, 1107, 1067, 1017, 844, 757, 598 cm–1; LRMS-ESI (m/z): 587.43 [M + Na]+; HRMS (TOF-ES) (m/z): 565.2114 [M + H]+ calcd for C32H29F4N2O3, found 565.2116.

2-((2-Acetylphenyl)amino)-N-cyclohexyl-2-(2-fluorophenyl)acetamide (7ahd—Amide Cleaved Byproduct)

Chromatography purification (0–25% EtOAc in hexanes) gave 9.5 mg, 3.5%; pale yellow solid; mp 182–184 °C; 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.31–7.27 (m, 1H), 7.16–7.06 (m, 2H), 6.72 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 7.9 Hz, 1H), 5.21 (d, J = 5.1 Hz, 1H), 3.88–3.71 (m, 1H), 2.60 (s, 3H), 1.92 (d, J = 10.9 Hz, 1H), 1.81–1.60 (m, 4H), 1.38–1.24 (m, 2H), 1.22–0.96 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 201.4, 168.9, 160.8 (d, JC–F = 246.0 Hz), 149.2, 135.3, 132.8, 130.2 (d, JC–F = 8.4 Hz), 128.7 (d, JC–F = 3.6 Hz), 125.7 (d, JC–F = 14.1 Hz), 125.1 (d, JC–F = 3.5 Hz), 119.1, 116.3, 116.0 (d, JC–F = 21.9 Hz), 112.8, 56.6 (d, JC–F = 2.3 Hz), 48.5, 33.1, 32.9, 28.2, 25.6, 24.8, 24.8; IR (KBr) 3297, 3077, 2931, 2854, 1642, 1607, 1566, 1511, 1456, 1420, 1361, 1324, 1239, 1165, 1090, 1035, 954, 754, 628, 613 cm–1; LRMS-ESI (m/z): 391.34 [M + Na]+; HRMS (TOF-ES) (m/z): 369.1978 [M + H]+ calcd for C22H26FN2O2, found 369.1982.

Ethyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-phenylacetate (7aaa—Ethyl Ester)

Chromatography purification (0–20% EtOAc in hexanes) gave 208 mg, 66%; off-white solid; mp 206–208 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.4 Hz, 2H), 7.84 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.51–7.44 (m, 3H), 7.44–7.40 (m, 2H), 7.36–7.26 (m, 4H), 7.23 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) 195.3, 168.6, 160.0, 145.3, 138.6, 136.8, 134.0, 133.7, 131.1, 130.6, 129.5, 129.3, 128.9, 128.6, 128.2, 128.1, 127.2, 126.1, 123.0, 121.5, 116.1, 62.1, 58.8, 16.3, 14.1; IR (KBr) 3299, 2930, 1746, 1675, 1639, 1597, 1568, 1499, 1455, 1387, 1368, 1318, 1266, 1206, 1170, 1030, 752, 697, 664 cm–1; LRMS-ESI (m/z): 448.30 [M + Na]+; HRMS (TOF-ES) (m/z): 426.1705 [M + H]+ calcd for C27H24NO4, found 426.1705.

Propyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-phenylacetate (7aaa—Propyl Ester)

Chromatography purification (0–20% EtOAc in hexanes) gave 170 mg, 52%; off-white solid; mp 205–207 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.6 Hz, 2H), 7.84 (dd, J = 8.0, 1.3 Hz 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.45–7.40 (m, 3H), 7.32 (t, J = 7.1 Hz, 2H), 7.30–7.25 (m, 2H), 7.21 (d, J = 8.6 Hz, 1H), 7.07 (s, 1H), 4.08 (t, J = 6.6 Hz, 2H), 2.43 (s, 3H), 1.58–1.45 (m, 2H), 0.72 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 195.3, 168.7, 160.0, 145.3, 138.5, 136.8, 134.0, 133.7, 131.1, 130.6, 129.4, 128.9, 128.6, 128.2, 128.1, 126.1, 122.9, 121.4, 116.3, 67.6, 58.4, 21.8, 16.3, 10.3; IR (KBr) 2967, 1744, 1676, 1638, 1596, 1568, 1498, 1456, 1389, 1316, 1266, 1205, 1170, 837, 821, 752, 696, 664 cm–1; LRMS-ESI (m/z): 462.30 [M + Na]+; HRMS (TOF-ES) (m/z): 440.1862 [M + H]+ calcd for C28H26NO4, found 440.1862.

Butyl 2-(3-benzoyl-4-methyl-2-oxoquinolin-1(2H)-yl)-2-phenylacetate (7aaa—Butyl Ester)

Chromatography purification (0–20% EtOAc in hexanes) gave 158 mg, 47%; off-white solid; mp 119–121 °C; 1H NMR (400 MHz, CDCl3) δ 7.98–7.90 (m, 2H), 7.84 (dd, J = 8.1, 1.5 Hz, 1H), 7.63–7.56 (m, 1H), 7.50–7.45 (m, 2H), 7.45–7.40 (m, 3H), 7.36–7.30 (m, 2H), 7.30–7.26 (m, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.08 (s, 1H), 4.16–4.09 (m, 2H), 2.43 (s, 3H), 1.51–1.41 (m, 2H), 1.18–1.07 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 195.2, 168.8, 160.0, 145.2, 138.6, 136.9, 133.9, 133.7, 131.0, 130.7, 129.4, 128.9, 128.6, 128.2, 128.1, 126.1, 122.9, 121.5, 116.4, 65.9, 58.4, 30.5, 19.0, 16.3, 13.7; IR (KBr) 2959, 2929, 2871, 2854, 1743, 1676, 1639, 1597, 1569, 1498, 1455, 1387, 1317, 1266, 1204, 1170, 1066, 752, 696, 664 cm–1 LRMS-ESI (m/z): 476.39 [M + Na]+; HRMS (TOF-ES) (m/z): 454.2018 [M + H]+ calcd for C29H28NO4, found 454.2022.