Abstract
Synthesis of 2,3-disubstituted 4-ethoxycarbonyl-β-carbolin-1-ones is developed using palladium-catalyzed intramolecular amination of 3-amino-4-(2-bromophenyl)-2-pyridones prepared by the conjugate addition reaction of diethyl 2-aminomalonate to alkynyl imines. The method was applied to the total syntheses of SL651498 exhibiting anxiolytic activity and its analogue.
Introduction
β-Carbolin-1-ones have increasingly attracted attention in recent years owing to their biological activities. The β-carbolin-1-one skeleton is found in many alkaloids, such as Bauerine C and Secofascaplysin A.1,2 In addition, 4-carbonyl-β-carbolin-1-ones are known to display strong biological activity. For example, SL651498 displays anxiolytic activity.3 It has been reported that β-carbolin-1-ones are also effective as antidiabetic agents4 and ATAD2 inhibitors5 (Figure 1).
Figure 1.
Examples of biologically active β-carbolin-1-one alkaloids and 4-carbonyl-β-carbolin-1-ones.
There are several synthetic methods for β-carbolin-1-ones,6 including intramolecular Diels–Alder reaction,7 cross-coupling,8 cycloisomerization,9 and annulation of pyridone rings.10 Recently, several other synthetic methods for β-carbolin-1-ones have also been reported. In 2016, Swamy et al. reported the synthesis of these compounds via phase-transfer-catalyzed intramolecular cyclization of 3-alkynylindole-2-carboxamides.11 In 2018, Dömling et al. reported a mild and facile one-pot procedure for the synthesis of β-carbolin-1-ones.12 In 2019, Xia and co-workers reported the synthesis of β-carbolin-1-ones via Pd/Cu-co-catalyzed oxidative tandem C–H aminocarbonylation and dehydrogenation of tryptamines.13 In the same year, Fillery et al. reported the one-pot tandem Buchwald–Hartwig/Heck reaction for the synthesis of these compounds.5 However, to the best of our knowledge, a synthetic method for 4-carbonyl-β-carbolin-1-ones that have various substituents at the 3-position has not been reported as yet and the effect of substituents at the 3-position on the biological activity is not known. Therefore, the development of a new synthetic method for 3-substituted 4-carbonyl-β-carbolin-1-ones is highly desired.
We have previously reported the synthesis of multisubstituted 2-pyridones via conjugate addition of malonates to alkynyl imines and their applications (Scheme 1a).14 Further investigation into the synthesis of heterocycles using alkynyl imines revealed that the reaction of alkynyl imines with 2-aminomalonate yielded multisubstituted 3-amino-5-ethoxycarbonyl-2-pyridones (Scheme 1b). Fortunately, this reaction tolerated more functional groups like aryl, heteroaryl, and alkenyl at the 3-position than those in our previous study. Several synthetic methods for 3-amino-2-pyridones have been reported.15 However, there are few examples of multiple substituents being introduced simultaneously on the 2-pyridone ring. Herein, we report the synthesis of 2,3-disubstituted 4-ethoxycarbonyl-β-carbolin-1-ones using multisubstituted 3-amino-5-ethoxycarbonyl-2-pyridone synthesis as a key reaction.
Scheme 1. Our Previous Work and Synthesis of Multisubstituted 3-Amino-5-ethoxycarbonyl-2-pyridones.
Results and Discussion
Scheme 2 shows the synthetic plan for 2,3-disubstituted 4-ethoxycarbonyl-β-carbolin-1-ones 1. These compounds could be obtained by the intramolecular amination of 3-amino-4-(2-bromophenyl)-2-pyridones 2. Substrates 2 could be synthesized by the deprotection of 3-amino-4-(2-bromophenyl)-2-pyridones 3, which could be obtained by the conjugate addition of diethyl 2-aminomalonate 5 to alkynyl imines 4 with a bromo group for the coupling reaction (Scheme 2).
Scheme 2. Retrosynthetic Analysis of 2,3-Disubstituted 4-Ethoxycarbonyl-β-carbolin-1-ones.
Initially, we screened the reaction conditions for the synthesis of 3-amino-2-pyridone 3 (Table 1). Decarboxylated 3-amino-2-pyridone 6 was obtained using 2-aminomalonate 5a as a nucleophile in 1,4-dioxane at reflux (entries 1 and 2). When nucleophile 5a was changed to 2-aminomalonate 5b having a smaller protecting group, 3 was selectively obtained in 26% yield (entry 3). Subsequently, the effect of the ratio of 5b and several bases was studied (entries 4–11). The experimental results showed that 5b (2.0 equiv) and KHMDS (1.0 equiv) were the most suitable for the synthesis of 3 (entry 4).
Table 1. Optimization of Conjugate Addition Reactiona.
Conditions: 4a (0.1 mmol), 1,4-dioxane (4 mL).
In 1,4-dioxane-toluene (20:1, 4.2 mL).
In 1,4-dioxane-THF (4.3:1, 4.9 mL).
The yields were determined by 1H NMR spectra using phenanthrene as an internal standard.
Under the optimized reaction conditions, several alkynyl imines were subjected to the conjugate addition reaction and subsequent deprotection. The results are summarized in Scheme 3. The reaction of alkynyl imine 4a under the optimized reaction conditions gave 2a in 72% yield. We next examined substrates with different aromatic substituents on the imino nitrogen (R1). Alkynyl imines 4b and 4c with p- or m-tolyl groups produced 3-amino-2-pyridones 2b and 2c, respectively, in good yields. The reaction of 4d with an o-tolyl group gave 2d in 33% yield because of steric hindrance. Substrate 4e with an electron-donating group produced 2e in 39% yield, while 4f bearing an electron-withdrawing group gave 2f in 68% yield. We next examined substrates with different substituents on the imino carbon (R2). Alkynyl imines 4g–4i having tolyl groups produced 3-amino-2-pyridones 2g–2i, respectively, in good yields. Substrates 4j and 4k with electron-donating and electron-withdrawing groups produced 2j and 2k in 79 and 73% yields, respectively. The reactions of 4l and 4m with heteroaromatic groups such as 2-furyl and 2-thienyl proceeded to give 2l and 2m, respectively, in good yields. The reaction of alkynyl imine 4n with a styryl group proceeded regioselectively to afford 2n in 69% yield. The alkynyl imine 4o bearing two electron-donating groups gave 2o in 34% yield probably because the electrophilicity at β-carbon of 4o decreased. Further investigation showed that alkynyl aldimine 4p afforded 2p in 58% yield. Finally, we examined the substrates with different aromatic substituents R3. The reactions of alkynyl imines 4q and 4r with a fluoro group for the syntheses of SL651498 and its analogue gave 2q and 2r, respectively, in good yields.
Scheme 3. Substrate Scope in the Conjugate Addition Reaction.
Conditions: 4 (1.0 mmol), 5b (2.0 mmol), KHMDS (1.0 mmol), 1,4-dioxane-toluene (20:1, 42 mL), reflux, 1.5 h. Then, 1 M H2SO4 (10 mL), reflux, 6 h.
Conditions: 4 (0.5 mmol), 5b (1.0 mmol), KHMDS (0.5 mmol), 1,4-dioxane-toluene (20:1, 21 mL), reflux, 1.5 h. Then, 1 M H2SO4 (5 mL), reflux, 6 h.
Conditions: 4 (0.3 mmol), 5b (0.6 mmol), KHMDS (0.3 mmol), 1,4-dioxane-toluene (20:1, 12.6 mL), reflux, 1.5 h. Then, 1 M H2SO4 (3 mL), reflux, 6 h.
Conditions: 1 (0.2 mmol), 5b (0.4 mmol), KHMDS (0.2 mmol), 1,4-dioxane-toluene (20:1, 8.4 mL), reflux, 1.5 h. Then, 1 M H2SO4 (2 mL), reflux, 6 h.
A plausible reaction mechanism for the synthesis of 3-amino-2-pyridones 2, 3, and 6 is shown in Scheme 4. First, metalloallenamine B would be generated by the conjugate addition of potassium diethyl 2-aminomalonate A to alkynyl imine 4. In the reaction of 5b having a smaller protecting group, cyclobutenoxide C would be formed by intramolecular cyclization and then transformed into metalloenamine D by a ring-opening reaction. The subsequent intramolecular cyclization would lead to the formation of 3. The deprotection of 3 under acidic conditions finally would afford 2 (path a). In the reaction of 5a possessing a larger one, the intramolecular cyclization to give C would not proceed due to the steric hindrance. Therefore, the α,β-unsaturated imine E would be generated by the protonation of metalloallenamine B with diethyl 2-aminomalonate 5a because the active methine proton of 5a is more acidic than that of 5b. The decarboxylated 3-amino-2-pyridone 6 and diethyl carbonate would be formed by the nucleophilic addition of potassium ethoxide to the ethoxycarbonyl group of E (path b).16
Scheme 4. Possible Reaction Mechanism.
We examined the transformation of the synthesized 3-amino-2-pyridones 2 to β-carbolin-1-ones 1 via palladium-catalyzed intramolecular amination under the conditions reported by Buchwald.17,18 We first examined the amination reaction using Sphos as a commercially available Buchwald phosphine ligand. These results are summarized in Scheme 5. The reaction of 2a proceeded smoothly to give 1a in 83% yield. Next, we examined the effect of aromatic substituents R1 of 3-amino-2-pyridones 2 on the reaction. Compounds 2b–2d with p-, m-, or o-tolyl groups afforded β-carbolin-1-ones 1b–1d, respectively, in good to high yields. Further, while substrate 2e with an electron-donating group gave 1e in 85% yield, 2f with an electron-withdrawing group afforded 1f in 59% yield. We also examined 3-amino-2-pyridone substrates with different R2 substituents. Compounds 2g–2i having p-, m-, or o-tolyl groups produced 1g–1i in good yields, respectively. 3-Amino-2-pyridones 2j and 2k with electron-donating and electron-withdrawing groups gave 1j and 1k in 93 and 84% yields, respectively. The reaction of 2l and 2m with heteroaromatic groups gave 1l and 1m, respectively, in good yields. Substrate 2n with a styryl group afforded 1n in 68% yield, and the reaction of 2o that possessed two electron-donating groups gave 1o in 67% yield. Further, substrate 2p lacked a substituent at the 6-position and its transformation afforded β-carbolin-1-one 1p in 74% yield. Finally, we examined the transformation of 3-amino-2-pyridones 2 with different R3 substituents; 2q and 2r with fluoro groups produced β-carbolin-1-ones 1q and 1r, respectively, in high yields.
Scheme 5. Substrate Scope in Intramolecular Amination.
Conditions: 2 (0.1 mmol), Pd2(dba)3 (0.0025 mmol), SPhos (0.0075 mmol), NaOtBu (0.2 mmol), 1,4-dioxane (2 mL), reflux, 4 h.
Conditions: See the Experimental Section for details.
We also examined the syntheses of SL651498 and its analogue 11 from β-carbolin-1-ones 1q and 1r, respectively (Scheme 6). First, N-methylation at the 9-position of β-carbolin-1-ones 1q and 1r afforded the corresponding N-methylated β-carbolin-1-ones 7 and 8 in 74 and 97% yields, respectively. In the next step, hydrolysis of 7 and 8 gave carboxylic acids 9 and 10 in 95 and 62% (95% brsm) yields, respectively.19 Finally, amidation of 9 and 10 led to excellent yields of SL61498 and its analogue 11, respectively, demonstrating their successful total syntheses.
Scheme 6. Syntheses of SL651498 and Its Analogue 11.
Conclusions
We have developed a synthetic method for 2,3-disubstituted 4-ethoxycarbonyl-β-carbolin-1-ones that involves the palladium-catalyzed intramolecular amination of 3-amino-4-(2-bromophenyl)-2-pyridones, which are prepared by the conjugate addition reaction of diethyl 2-aminomalonate to alkynyl imines with a bromo group followed by deprotection. The conjugate addition reactions between 2-aminomalonate 5b with an amidine-type protecting group as a nucleophile and alkynyl imines 4 proceeded smoothly to give the desired 3-amino-4-(2-bromophenyl)-2-pyridones 2 in moderate to good yields. The transformation of 3-amino-4-(2-bromophenyl)-2-pyridones 2 via palladium-catalyzed intramolecular amination afforded 2,3-disubstituted 4-ethoxycarbonyl-β-carbolin-1-ones 1 in good to excellent yields. The present β-carbolin-1-one synthesis is particularly attractive because multiple substituents can be introduced simultaneously on the 2-pyridone ring.
Experimental Section
General Aspects
Melting point (mp) determinations were performed using a YAMATO MP-21 instrument and are uncorrected. Infrared spectra were recorded on a JASCO FT/IR-460 Plus spectrometer. 1H NMR spectra were recorded on a JEOL JNM- ECX400P spectrometer (400 MHz) or a JNM-ECZ500R spectrometer (500 MHz). 13C{1H} NMR spectra were recorded on a JEOL JNM-ECX400P spectrometer (100 MHz) or a JEOL JNM-ECZ500R spectrometer (125 MHz). 19F NMR spectra were recorded on a JEOL JNM-ECZ500R spectrometer (470 MHz). Chemical shifts are reported in ppm relative to tetramethylsilane as an internal standard, CDCl3 (13C NMR δ 77.0), and dimethyl sulfoxide (DMSO, 1H NMR δ 2.50, 13C NMR δ 40.0) as an internal reference. High-resolution mass spectra (EI) were recorded on a JEOL JMS-700D mass spectrometer employed with a quadrupole doublet-based lens system. 1,4-Dioxane was distilled from CaH2 and stored over sodium. Dimethyl formamide (DMF) was distilled from calcium hydride and stored over molecular sieves 4 Å. Dichloromethane (DCM) was predried with P2O5, distilled from CaH2, and stored over molecular sieves 4 Å. Triethylamine (Et3N) was distilled from CaH2 and stored over molecular sieves 4 Å. Purification of products was performed by column chromatography on silica gel (Kanto Chemical Co., Inc., Silica Gel 60 N (spherical, neutral)) and/or preparative thin-layer chromatography (TLC) on silica gel (Wakogel B-5F). All reactions were carried out under an argon atmosphere. For reactions that require heating, an oil bath was used.
Synthesis of 2-Aminomalonates 5
In a 100 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon was placed diethyl aminomalonate hydrochloride S1 (3.62 g, 17.1 mmol), and to it were added dichloromethane (60 mL) and benzophenoneimine (3.13 g, 17.1 mmol) at room temperature. The mixture was stirred at room temperature for 24 h. The mixture was filtered through a Celite pad. The Celite pad was washed with dichloromethane (30 mL). The solvent was evaporated in vacuo. Water (60 mL) was added and then the mixture was extracted with diethyl ether (60 mL × 2). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 10:1) to give 2-aminomalonate 5a (4.67 g, 80%).
Diethyl 2-((Diphenylmethylene)amino)malonate (5a)20
White solid;
mp 43-45 °C
(lit. 39 °C); 1H NMR (500 MHz, CDCl3) δ
7.71–7.69 (m, 2H), 7.47–7.45 (m, 3H), 7.43–7.40
(m, 1H), 7.35–7.32 (m, 2H), 7.21–7.19 (m, 2H), 4.85
(s, 1H), 4.30–4.20 (m, 4H), 1.28 (t, J = 7.2
Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 173.8, 167.2, 138.9, 135.4, 130.8, 129.2, 129.1, 128.6,
128.0, 127.7, 69.6, 61.8, 14.0; IR (KBr) 3060, 2980, 2918, 1765, 1729,
1660, 1625, 1596, 1576, 1490, 1464, 1446, 1389, 1368, 1342, 1319,
1279, 1212, 1148, 1094, 1027, 909, 858, 784, 742, 710, 701 cm–1; HRMS (EI): calcd for C20H21NO4 (M)+ 339.1471, found 339.1487.
In a 500 mL two-neck round-bottom flask equipped with a magnetic stirring bar was placed diethyl aminomalonate hydrochloride S1 (6.35 g, 30.0 mmol), and to it was added saturated aqueous NaHCO3 solution (150 mL) at room temperature. The mixture was stirred at room temperature for 3 min. The mixture was extracted with DCM (60 mL × 3). The solvent was evaporated and dried in vacuo to give the crude 2-aminomalonate. In a 200 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed the crude 2-aminomalonate, and to it were added toluene (60 mL) and (MeO)2CNMe2 (4.64 mg, 39.0 mmol) at room temperature. The mixture was stirred under reflux for 30 min and then at room temperature for 12 h. The excess (MeO)2CNMe2 and the solvents were evaporated in vacuo to give diethyl 2-aminomalonate 5b (6.23 g, 90%).
Diethyl (E)-2-(((Dimethylamino)methylene)amino)malonate (5b)21
Yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 4.51 (s, 1H), 4.20–4.16 (m, 4H), 2.87 (s, 6H), 1.23 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.6, 157.9, 70.0, 60.9, 39.6, 33.8, 13.6; IR (neat) 2983, 2931, 1739, 1643, 1440, 1377, 1307, 1206, 1087, 1035, 956, 860, 778, 725 cm–1; HRMS (EI): calcd for C10H18N2O4 (M)+ 230.1267, found 230.1258.
Synthesis of Alkynyl Imines 4
Alkynyl
imines 4a,4b, 4e, 4f, 4g, 4j, 4k, 4l, 4m, 4n, 4o, and 4r were prepared using copper-catalyzed reactions of terminal alkynes
with nitrones according to the literature method.22 Alkynyl imines 4c,4d, 4h, and 4i were synthesized using palladium-catalyzed
reactions of terminal alkynes with imidoyl chlorides according to
the literature method.23
In a 50 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3a(24) (686 mg, 3.48 mmol), CuI (66.3 mg, 0.348 mmol), 1,2-bis(diphenylphosphino)ethane (DPPE, 139 mg, 0.348 mmol), and K2CO3 (529 mg, 3.83 mmol), and to it were added H2O (0.13 mL, 6.96 mmol) and 1-bromo-2-ethynylbenzene S2a(25) (629 mg, 3.48 mmol) in DMF (14 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. H2O (25 mL) was added to quench the reaction. The mixture was extracted with Et2O (40 mL × 2). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 3:1) to give alkynyl imine 4a (739 mg, 59%).
(Z)-3-(2-Bromophenyl)-N,1-diphenylprop-2-yn-1-imine (4a)
Yellow solid; mp 77–79 °C; 1H NMR (400 MHz, CDCl3) δ 8.35–8.33
(m, 2H), 7.58–7.47 (m, 4H), 7.43–7.39 (m, 2H), 7.25–7.17
(m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.7, 149.8, 137.0, 134.6, 132.5, 131.2, 130.8, 128.6,
128.4, 128.3, 127.1, 125.9, 124.8, 123.8, 120.8, 95.4, 86.8; IR (KBr)
3055, 2962, 2924, 2206, 1551, 1482, 1468, 1447, 1322, 1274, 1265,
1197, 1176, 1082, 1053, 1014, 918, 809, 761 cm–1; HRMS (EI): calcd for C21H14BrN (M)+ 359.0310, found 359.0310.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3b(26) (634 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it were added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (10 mL) were added to quench the reaction. The mixture was extracted with Et2O (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 3:1) to give alkynyl imine 4b (508 mg, 45%).
(Z)-3-(2-Bromophenyl)-1-phenyl-N-(p-tolyl)prop-2-yn-1-imine (4b)
Yellow solid; mp 98–100 °C; 1H
NMR (400
MHz, CDCl3) δ 8.34–8.32 (m, 2H), 7.58–7.56
(m, 1H), 7.51–7.45 (m, 3H), 7.31–7.14 (m, 7H), 2.38
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 149.0, 148.9, 137.3, 134.7, 134.6, 132.6, 131.0, 130.7,
129.1, 128.4, 128.2, 127.1, 125.9, 124.0, 121.1, 95.1, 87.1, 21.1;
IR (KBr) 3025, 2912, 2858, 2199, 1579, 1551, 1503, 1468, 1438, 1319,
1274, 1194, 1173, 1114, 1053, 1014, 854, 815, 762, 692 cm–1; HRMS (EI): calcd for C22H16BrN (M)+ 373.0466, found 373.0485.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed amine S4c (1.07 g, 10.0 mmol), and to it were added DCM (15 mL) and Et3N (2.13 g, 21.0 mmol) at room temperature. The mixture was stirred at room temperature for 5 min and then added acyl chloride S5c (1.55 g, 11.0 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo, and then the residue was washed by H2O (20 mL) and purified by recrystallization with EtOH to give amide S3c (1.08 g, 51%).
N-(m-Tolyl)benzamide (S3c)27
White solid; mp 120–122 °C (lit. 119–120 °C); 1H NMR (500 MHz, CDCl3) δ 7.87–7.85 (m, 2H), 7.82 (brs, 1H), 7.56–7.46 (m, 4H), 7.41 (d, J = 8.0 Hz, 1H), 7.26–7.23 (m, 1H), 6.97 (d, J = 7.5 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.7, 139.0, 137.8, 135.1, 131.8, 128.9, 128.8, 127.0, 125.4, 120.8, 117.2, 21.5; IR (KBr) 3263, 3059, 1965, 1941, 1851, 1776, 1648, 1579, 1531, 1485, 1430, 1302, 1258, 1169, 1073, 1027, 1001, 975, 867, 747, 711 cm–1; HRMS (EI): calcd for C14H13NO (M)+ 211.0997, found 211.0999.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed amide S3c (634 mg, 3.00 mmol) in thionyl chloride (1.43 g, 12.0 mmol) at room temperature. The reaction mixture was stirred at reflux for 1.5 h and then cooled to room temperature. The excess thionyl chloride and volatile materials were evaporated and dried in vacuo to give the crude imidoyl chloride (651 mg). In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed Pd(OAc)2 (6.7 mg, 0.03 mmol), PPh3 (7.9 mg, 0.03 mmol), and the crude imidoyl chloride in degassed triethylamine (7 mL) at room temperature, and to the mixture was added 1-bromo-2-ethynylbenzene S2a (543 mg, 3.0 mmol). The reaction mixture was stirred at 80 °C for 2 h and then cooled to room temperature. The mixture was diluted with Et2O (10 mL) and filtered through a Celite pad. The Celite pad was washed with Et2O (20 mL). The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 98:2) to give alkynyl imine 4c (817 mg, 73%, two steps).
(Z)-3-(2-Bromophenyl)-1-phenyl-N-(m-tolyl)prop-2-yn-1-imine (4c)
Yellow solid; mp 77–78 °C; 1H NMR
(400 MHz,
CDCl3) δ 8.34–8.32 (m, 2H), 7.57–7.47
(m, 4H), 7.34–7.17 (m, 4H), 7.01–6.99 (m, 3 H), 2.39
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.6, 149.5, 138.3, 137.1, 134.6, 132.5, 131.1, 130.8,
128.4, 128.4, 128.2, 127.1, 125.9, 125.7, 123.9, 121.4, 117.8, 95.3,
86.9, 21.5; IR (KBr) 3056, 2915, 2860, 2199, 1456, 1308, 1251, 1208,
1156, 1017, 866, 783, 771, 759, 695 cm–1; HRMS (EI):
calcd for C22H16BrN (M)+ 373.0466,
found 373.0467.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed amide S3d(27) (634 mg, 3.00 mmol) in thionyl chloride (1.43 g, 12.0 mmol) at room temperature. The reaction mixture was stirred at reflux for 1.5 h and then cooled to room temperature. The excess thionyl chloride and volatile materials were evaporated and dried in vacuo to give the crude imidoyl chloride (642 mg). In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed Pd(OAc)2 (6.7 mg, 0.03 mmol), PPh3 (7.9 mg, 0.03 mmol), and the crude imidoyl chloride in degassed triethylamine (7 mL) at room temperature, and to the mixture was added 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol). The reaction mixture was stirred at 80 °C for 2 h and then cooled to room temperature. The mixture was diluted with Et2O (10 mL) and filtered through a Celite pad. The Celite pad was washed with Et2O (20 mL). The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 98:2) to give alkynyl imine 4d (901 mg, 80%, two steps).
(Z)-3-(2-Bromophenyl)-1-phenyl-N-(o-tolyl)prop-2-yn-1-imine (4d)
White solid; mp 64–66 °C; 1H NMR
(400 MHz,
CDCl3) δ 8.38–8.35 (m, 2H), 7.55–7.48
(m, 4H), 7.29–7.02 (m, 7H), 2.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.7, 149.6, 136.9,
134.7, 132.5, 131.2, 130.8, 130.1, 129.1, 128.4, 128.2, 127.1, 126.0,
125.9, 124.6, 123.9, 119.1, 95.3, 86.8, 17.9; IR (KBr) 3055, 3014,
2913, 2207, 1588, 1558, 1481, 1469, 1381, 1320, 1308, 1248, 1210,
1178, 1108, 1053, 1025, 1014, 932, 846, 769, 748, 716 cm–1; HRMS (EI): calcd for C22H16BrN (M)+ 373.0466, found 373.0468.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed H2O (50 mL), EtOH (50 mL), NH4Cl (535 mg, 10.0 mmol), aldehyde S5e (1.06 g, 10.0 mmol), and nitroarene S4e (1.53 g, 10.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 min, and to it was added Zn powder (1.31 g, 20.0 mmol) at 0 °C and then stirred at room temperature for 15 h. The mixture was filtered through a Celite pad. The Celite pad was washed with DCM (50 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 2:1) to give nitrone S3e (1.12 g, 49%).
(Z)-N-(4-Methoxyphenyl)-1-phenylmethanimine Oxide (S3e)
Yellow solid; mp 123–125 °C; 1H NMR (500 MHz, CDCl3) δ 8.39–8.38 (m, 2H), 7.87 (s, 1H), 7.74–7.72 (m, 2H), 7.50–7.45 (m, 3H), 6.97–6.95 (m, 2H), 3.87 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 160.6, 142.5, 133.7, 130.9, 130.7, 128.9, 128.6, 123.0, 114.0, 55.6; IR (KBr) 3053, 2960, 2837, 1598, 1547, 1503, 1442, 1393, 1302, 1245, 1194, 1083, 1069, 1033, 924, 889, 841, 812, 749 cm–1; HRMS (EI): calcd for C14H13NO2 (M)+ 227.0946, found 227.0937.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3e (682 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it were added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (25 mL) were added to quench the reaction. The mixture was extracted with Et2O (30 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 3:1) to give alkynyl imine 4e (632 mg, 54%).
(Z)-3-(2-Bromophenyl)-N-(4-methoxyphenyl)-1-phenylprop-2-yn-1-imine (4e)
Yellow solid; mp 101–103 °C; 1H NMR (400 MHz, CDCl3) δ 8.34–8.32
(m, 2H), 7.60–7.58 (m, 1H), 7.50–7.47 (m, 3H), 7.37–7.35
(m, 1H), 7.33–7.30 (m, 2H), 7.28–7.20 (m, 2 H), 6.96–6.94
(m, 2H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 157.5, 148.1, 144.3, 137.5, 134.5, 132.6,
130.9, 130.8, 128.4, 128.1, 127.1, 125.9, 124.0, 123.0, 113.8, 94.9,
87.3, 55.5; IR (KBr) 2907, 2828, 2204, 1594, 1550, 1500, 1467, 1319,
1285, 1241, 1188, 1109, 1025, 851, 815, 760 cm–1; HRMS (EI): calcd for C22H16BrNO (M)+ 389.0415, found 389.0404.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3f(28) (695 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it were added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (25 mL) were added to quench the reaction. The mixture was extracted with Et2O (30 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 3:1) to give alkynyl imine 4f (834 mg, 70%).
(Z)-3-(2-Bromophenyl)-N-(4-chlorophenyl)-1-phenylprop-2-yn-1-imine (4f)
Yellow solid; mp 107–108 °C; 1H NMR (400 MHz, CDCl3) δ 8.33–8.30
(m, 2H), 7.60–7.58 (m, 1H), 7.53–7.47 (m, 3H), 7.38–7.36
(m, 2H), 7.30–7.21 (m, 3H), 7.16–7.12 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
150.3, 150.1, 136.8,134.6, 132.7, 131.5, 131.1, 130.2, 128.7, 128.5,
128.3, 127.2, 126.0, 123.6, 122.4, 96.0, 86.5; IR (KBr) 3053, 2199,
1559, 1473, 1315, 1187, 1085, 1017, 851, 812, 767, 753 cm–1; HRMS (EI): calcd for C21H13BrClN (M)+ 392.9920, found 392.9923.
In a 300 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed H2O (50 mL), EtOH (50 mL), NH4Cl (535 mg, 10.0 mmol), aldehyde S5g (1.20 g, 10.0 mmol), and nitroarene S4g (1.23 g, 10.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 min, and to it was added Zn powder (1.31 g, 20.0 mmol) at 0 °C and then stirred at room temperature for 15 h. The mixture was filtered through a Celite pad. The Celite pad was washed with DCM (50 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 2:1) to give nitrone S3g (870 mg, 41%).
(Z)-N-Phenyl-1-(p-tolyl)methanimine Oxide (S3g)29
Yellow solid; mp 75–77 °C (lit. 84–86 °C); 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.0 Hz, 2H), 7.89 (s, 1H), 7.78–7.76 (m, 2H), 7.49–7.43 (m, 3H), 7.29 (d, J = 7.7 Hz, 2H), 2.42 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 149.1, 141.5, 134.6, 129.7, 129.4, 129.1, 128.1, 121.7, 21.8; IR (KBr) 2927, 1725, 1597, 1557, 1458, 1404, 1289, 1190, 1067, 844, 756 cm–1; HRMS (EI): calcd for C14H13NO (M)+ 211.0997, found 211.1006.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3g (634 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it were added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (10 mL) were added to quench the reaction. The mixture was extracted with Et2O (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 2:1) to give alkynyl imine 4g (556 mg, 50%).
(Z)-3-(2-Bromophenyl)-N-phenyl-1-(p-tolyl)prop-2-yn-1-imine (4g)
Yellow
solid; mp 87–89 °C; 1H NMR (400 MHz, CDCl3) δ 8.23–8.21
(m, 2H), 7.58–7.54 (m, 1H), 7.41–7.37 (m, 2H), 7.31–7.29
(m, 2H), 7.24–7.15 (m, 6H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.9, 149.7, 141.7, 134.6,
134.5, 132.5, 130.8, 129.2, 128.6, 128.3, 127.1, 125.9, 124.7, 123.9,
120.8, 95.2, 87.0, 21.5; IR (KBr) 3053, 3020, 2921, 2208,
1928, 1811, 1743, 1577, 1555, 1481, 1469, 1453, 1319, 1276, 1276,
1210, 1194, 1174, 1114, 1053, 1024, 1014, 958, 906, 823, 758, 718,
691 cm–1; HRMS (EI): calcd for C22H16BrN (M)+ 373.0466, found 373.0483.
In a 300 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed amine S4h (931 mg, 10.0 mmol), and to it were added DCM (15 mL) and Et3N (2.13 g, 21.0 mmol) at room temperature. The mixture was stirred at room temperature for 5 min and then added acyl chloride S5h (1.70 g, 11.0 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo, and then the residue was washed by H2O (20 mL) and purified by recrystallization with EtOH to give amide S3h (1.68 g, 80%).
3-Methyl-N-phenylbenzamide (S3h)27
White solid; mp 122–124 °C (lit. 124–125 °C); 1H NMR (500 MHz, CDCl3) δ 7.91 (brs, 1H), 7.67–7.63 (m, 4H), 7.36–7.33 (m, 4H), 7.15–7.12 (m, 1H), 2.40 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.0, 138.6, 138.0, 135.0, 132.5, 129.0, 128.6, 127.8, 124.5, 123.9, 120.2, 21.3; IR (KBr) 3247, 3194, 3128, 3062, 1650, 1602, 1541, 1488, 1442, 1328, 1275, 1241, 1084, 937, 907, 889, 844, 808, 759, 728 cm–1; HRMS (EI): calcd for C14H13NO (M)+ 211.0997, found 211.1000.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed amide S3h (634 mg, 3.00 mmol) in thionyl chloride (1.43 g, 12.0 mmol) at room temperature. The reaction mixture was stirred at reflux for 1.5 h and then cooled to room temperature. The excess thionyl chloride and volatile materials were evaporated and dried in vacuo to give the crude imidoyl chloride (652 mg). In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed Pd(OAc)2 (6.7 mg, 0.03 mmol), PPh3 (7.9 mg, 0.03 mmol), and the crude imidoyl chloride in degassed triethylamine (7 mL) at room temperature, and to the mixture was added 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol). The reaction mixture was stirred at 80 °C for 2 h and then cooled to room temperature. The mixture was diluted with Et2O (10 mL) and filtered through a Celite pad. The Celite pad was washed with Et2O (20 mL). The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 98:2) to give alkynyl imine 4h (681 mg, 61%, two steps).
(Z)-3-(2-Bromophenyl)-N-phenyl-1-(m-tolyl)prop-2-yn-1-imine (4h)
Yellow
solid; mp 78–89 °C; 1H NMR (400 MHz, CDCl3) δ 8.18–8.12 (m, 2H), 7.56–7.54 (m, 1H),
7.42–7.31 (m, 4H), 7.23–7.16 (m, 6H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
151.8, 150.0, 138.1, 137.0, 134.6, 132.5, 132.1, 130.8, 128.7, 128.6,
128.3, 127.1, 125.9, 125.7, 124.8, 123.9, 120.8, 95.4, 87.0, 21.4;
IR (KBr) 3052, 2966, 2922, 2860, 2202, 1946, 1806, 1739, 1585, 1577,
1552, 1482, 1469, 1450, 1438, 1321, 1277, 1260, 1204, 1182, 1167,
1072, 1054, 1026, 908, 902, 838, 797, 784, 761, 707, 693 cm–1; HRMS (EI): calcd for C22H16BrN (M)+ 373.0466, found 373.0469.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed amide S3i(27) (634 mg, 3.00 mmol) in thionyl chloride (1.43 g, 12.0 mmol) at room temperature. The reaction mixture was stirred at reflux for 1.5 h and then cooled to room temperature. The excess thionyl chloride and volatile materials were evaporated and dried in vacuo to give the crude imidoyl chloride (652 mg). In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed Pd(OAc)2 (6.7 mg, 0.03 mmol), PPh3 (7.9 mg, 0.03 mmol), and the crude imidoyl chloride in degassed triethylamine (7 mL) at room temperature, and to the mixture was added 1-bromo-2-ethynylbenzene S2a (664 mg, 3.00 mmol). The reaction mixture was stirred at 80 °C for 2 h and then cooled to room temperature. The mixture was diluted with Et2O (10 mL) and filtered through a Celite pad. The Celite pad was washed with Et2O (20 mL). The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 98:2) to give alkynyl imine 4i (941 mg, 84%, two steps).
(Z)-3-(2-Bromophenyl)-N-phenyl-1-(o-tolyl)prop-2-yn-1-imine (4i)
Yellow
solid; mp 50–52 °C; 1H NMR (400 MHz, CDCl3) δ 7.96–7.94 (m, 1H), 7.55–7.52 (m, 1H),
7.43–7.28 (m, 5H), 7.23–7.16 (m, 6H), 2.70 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
151.6, 137.3, 134.5, 132.5, 131.5, 130.8, 130.2, 129.8, 128.7, 127.0,
125.9, 125.9, 124.8, 123.9, 120.5, 95.3, 88.3, 21.4; IR (KBr) 3057,
2954, 2920, 2857, 2206, 1578, 1558, 1483, 1466, 1458, 1372, 1315,
1262, 1192, 1176, 1039, 1024, 1012, 906, 838, 782, 768, 755, 719,
693 cm–1; HRMS (EI): calcd for C22H16BrN (M)+ 373.0466, found 373.0454.
In a 300 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed H2O (50 mL), EtOH (50 mL), NH4Cl (535 mg, 10.0 mmol), aldehyde S5j (1.36 g, 10.0 mmol), and nitroarene S4g (1.23 g, 10.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 min, and to it was added Zn powder (1.31 g, 20.0 mmol) at 0 °C and then stirred at room temperature for 15 h. The mixture was filtered through a Celite pad. The Celite pad was washed with DCM (50 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 2:1) to give nitrone S3j (1.35 g, 59%).
(Z)-1-(4-Methoxyphenyl)-N-phenylmethanimine Oxide (S3j)29
Yellow solid; mp 105–107 °C (lit. 114–116 °C); 1H NMR (500 MHz, CDCl3) δ 8.42–8.39 (m, 2H), 7.86 (s, 1H), 7.78–7.77 (m, 2H), 7.49–7.43 (m, 3H), 7.01–6.99 (m, 2H), 3.88 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.5, 149.0, 134.1, 131.1, 129.6, 129.1, 123.8, 121.6, 114.0, 55.4; IR (KBr) 3058, 3006, 2928, 2844, 1726, 1602, 1551, 1508, 1459, 1398, 1308, 1257, 1179, 1064, 1027, 891, 849, 808, 772, 754 cm–1; HRMS (EI): calcd for C14H13NO2 (M)+ 227.0946, found 227.0948.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3j (682 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it was added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (25 mL) was added to quench the reaction. The mixture was extracted with Et2O (30 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 3:1) to give alkynyl imine 4j (455 mg, 39%).
(Z)-3-(2-Bromophenyl)-1-(4-methoxyphenyl)-N-phenylprop-2-yn-1-imine (4j)
Yellow
solid; mp 107–109 °C; 1H NMR (400 MHz, CDCl3) δ 8.30–8.28 (m, 2H), 7.58–7.55 (m, 1H),
741–7.37 (m, 2H), 7.25–7.15 (m, 6H), 7.01–6.99
(m, 2H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.2, 151.9, 149.1, 134.6, 132.5, 130.7,
130.0, 128.5, 127.1, 125.8, 124.5, 123.9, 120.9, 113.8, 95.1, 87.0,
55.4; IR (KBr) 3061, 3017, 2961, 2927, 2838, 2210, 1604, 1577, 1550,
1512, 1481, 1470, 1460, 1445, 1327, 1263, 1196, 1185, 1164, 1063,
1196, 1185, 1163, 1063, 1021, 902, 837, 756, 696 cm–1; HRMS (EI): calcd for C22H16BrNO (M)+ 389.0415, found 389.0403.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3k(28) (695 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it were added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (25 mL) were added to quench the reaction. The mixture was extracted with Et2O (30 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 3:1) to give alkynyl imine 4k (814 mg, 69%).
(Z)-3-(2-Bromophenyl)-1-(4-chlorophenyl)-N-phenylprop-2-yn-1-imine (4k)
Yellow
solid; mp 112–114 °C; 1H NMR (400 MHz, CDCl3) δ 8.29–8.27 (m, 2H), 7.58–7.57 (m, 1H),
7.47–7.46 (m, 2H), 7.42–7.39 (m, 2H), 7.26–7.17
(m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.4, 148.5, 137.4, 135.6, 134.7, 132.6, 131.0, 129.6,
128.7, 128.6, 127.1, 125.9, 125.1, 123.6, 120.8, 95.7, 86.5; IR (KBr)
3060, 2924, 2857, 2199, 1578, 1555, 1488, 1467, 1400, 1313, 1273,
1254, 1196, 1173, 1090, 1024, 1011, 846, 836, 756, 720 cm–1; HRMS (EI): calcd for C21H13BrClN (M)+ 392.9920, found 392.9909.
In a 200 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed H2O (50 mL), EtOH (50 mL), NH4Cl (535 mg, 10.0 mmol), aldehyde S5l (961 mg, 10.0 mmol), and nitroarene S4g (1.23 g, 10.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 min, and to it was added Zn powder (1.31 g, 20.0 mmol) at 0 °C and then stirred at room temperature for 15 h. The mixture was filtered through a Celite pad. The Celite pad was washed with DCM (50 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 2:1) to give nitrone S3l (1.22 g, 65%).
(Z)-1-(Furan-2-yl)-N-phenylmethanimine Oxide (S3l)
Yellow solid; mp 73–75 °C; 1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 8.01 (d, J = 3.4 Hz, 1H), 7.81–7.78 (m, 2H), 7.59–7.58 (m, 1H), 7.50–7.44 (m, 3H), 6.65–6.64 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 147.5, 147.3, 144.6, 129.9, 129.2, 124.2, 121.0, 116.4, 112.7; IR (KBr) 3099, 3060, 1570, 1546, 1475, 1389, 1238, 1154, 1069, 1018, 872, 823, 769, 744 cm–1; HRMS (EI): calcd for C11H9NO2 (M)+ 187.0633, found 187.0640.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3l (565 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it were added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (10 mL) were added to quench the reaction. The mixture was extracted with Et2O (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 2:1) to give alkynyl imine 4l (423 mg, 44%).
(E)-3-(2-Bromophenyl)-1-(furan-2-yl)-N-phenylprop-2-yn-1-imine (4l)
Yellow
oil; 1H NMR (400 MHz, CDCl3) δ 7.64–7.63
(m, 1H), 7.58–7.55 (m, 1H), 7.41–7.37 (m, 2H), 7.33–7.32
(m, 1H), 7.28–7.17 (m, 6H), 6.59–6.58 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
152.3, 150.5, 145.7, 139.1, 134.5, 132.6, 131.0, 128.5, 127.1, 125.9,
125.3, 123.4, 121.4, 116.8, 112.1; 93.1, 85.6; IR (neat) 3060, 2924,
2858, 2211, 1575, 1564, 1473, 1395, 1319, 1199, 1162, 1059, 1038,
1007, 832, 753, 696 cm–1; HRMS (EI): calcd for C19H12BrNO (M)+ 349.0102, found 349.0103.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3m(29) (613 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it were added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (10 mL) were added to quench the reaction. The mixture was extracted with Et2O (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 2:1) to give alkynyl imine 4m (326 mg, 30%).
(E)-3-(2-Bromophenyl)-N-phenyl-1-(thiophen-2-yl)prop-2-yn-1-imine (4m)
Yellow solid; mp 101–103 °C; 1H NMR (400 MHz, CDCl3) δ 7.96–7.95
(m, 1H), 7.59–7.56 (m, 1H), 7.51–7.49 (m, 1H), 7.41–7.37
(m, 2H), 7.29–7.14 (m, 8H); 13C{1H} NMR
(100 MHz, CDCl3) δ 150.6, 144.4, 143.8, 134.6, 132.6,
131.6, 131.0, 130.4, 128.5, 127.7, 127.1, 125.9, 125.2, 123.6, 121.4,
93.7, 86.0; IR (KBr) 3051, 2924, 2858, 2212, 1727, 1567, 1467, 1422,
1324, 1198, 1164, 1074, 1052, 1042, 1029, 976, 909, 834, 761, 718,
695 cm–1; HRMS (EI): calcd for C19H12BrNS (M)+ 364.9874, found 364.9861.
In a 300 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed H2O (50 mL), EtOH (50 mL), NH4Cl (535 mg, 10.0 mmol), aldehyde S5n (1.32 g, 10.0 mmol), and nitroarene S4g (1.23 g, 10.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 min, and to it was added Zn powder (1.31 g, 20.0 mmol) at 0 °C and then stirred at room temperature for 15 h. The mixture was filtered through a Celite pad. The Celite pad was washed with DCM (50 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 2:1) to give nitrone S3n (1.31 g, 59%).
(1Z,2E)-N,3-Diphenylprop-2-en-1-imine Oxide (S3n)
Yellow solid; mp 139–141 °C; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 9.7 Hz, 1H), 7.77–7.68 (m, 3H), 7.58–7.56 (m, 2H), 7.48–7.44 (m, 3H), 7.39–7.32 (m, 3H), 7.17 (d, J = 16.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 147.4, 140.0, 136.3, 136.1, 130.0, 129.5, 129.1, 128.9, 127.5, 121.4, 119.1; IR (KBr) 3058, 2925, 1950, 1887, 1834, 1684, 1600, 1519, 1480, 1377, 1301, 1189, 1055, 979, 879, 764, 746 cm–1; HRMS (EI): calcd for C15H13NO (M)+ 223.0997, found 233.0990.
In a 50 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3n (1.12 g, 5.00 mmol), CuI (95.2 mg, 0.500 mmol), DPPE (199 mg, 0.500 mmol), and K2CO3 (760 mg, 5.50 mmol), and to it were added DMF (15 mL), H2O (0.18 mL, 10.0 mmol), and 1-bromo-2-ethynylbenzene S2a (905 mg, 5.00 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (20 mL) were added to quench the reaction. The mixture was extracted with Et2O (30 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 2:1) to give alkynyl imine 4n (832 mg, 43%).
(1E,3Z)-5-(2-Bromophenyl)-N,1-diphenylpent-1-en-4-yn-3-imine (4n)
Yellow solid; mp 103–105 °C; 1H NMR (400 MHz,
CDCl3) δ 7.89–7.86 (m, 1H), 7.60–7.59
(m, 3H), 7.43–7.31 (m, 5H), 7.25–7.18 (m, 7H); 13C{1H} NMR (100 MHz, CDCl3) δ
151.2, 150.6, 142.0, 135.6, 134.6, 132.6, 130.8, 129.7, 129.5, 128.9,
128.5, 127.7, 127.2, 125.9, 125.2, 123.7, 121.2, 94.9, 85.7; IR (KBr)
3055, 2196, 1954, 1882, 1743, 1624, 1541, 1480, 1469, 1446, 1322,
1273, 1255, 1189, 1073, 1046, 1024, 971, 911, 859, 820, 770, 757,
690 cm–1; HRMS (EI): calcd for C23H16BrN (M)+ 385.0466, found 385.0466.
In a 300 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed H2O (50 mL), EtOH (50 mL), NH4Cl (535 mg, 10.0 mmol), aldehyde S5j (1.36 g, 10.0 mmol), and nitroarene S4e (1.53 g, 10.0 mmol) at room temperature. The mixture was stirred at room temperature for 15 min, and to it was added Zn powder (1.31 g, 20.0 mmol) at 0 °C and then stirred at room temperature for 15 h. The mixture was filtered through a Celite pad. The Celite pad was washed with DCM (50 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 2:1) to give nitrone S3o (1.18 g, 46%).
(Z)-N,1-Bis(4-methoxyphenyl)methanimine Oxide (S3o)30
Yellow solid; mp 138–140 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H), 7.73–7.71 (m, 2H), 7.00–6.95 (m, 4H), 3.88–3.86 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.3, 160.4, 142.3, 133.3, 131.0, 123.9, 122.8, 114.0, 55.6, 55.4; IR (KBr) 3049, 2945, 2838, 1604, 1506, 1463, 1306, 1253, 1179, 1110, 1070, 1026, 895, 849, 754 cm–1; HRMS (EI): calcd for C15H15NO3 (M)+ 257.1052, found 257.1041.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3o (772 mg, 3.00 mmol), CuI (57.1 mg, 0.300 mmol), DPPE (120 mg, 0.300 mmol), and K2CO3 (456 mg, 3.30 mmol), and to it were added DMF (9 mL), H2O (0.11 mL, 6.10 mmol), and 1-bromo-2-ethynylbenzene S2a (543 mg, 3.00 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (20 mL) was added to quench the reaction. The mixture was extracted with Et2O (30 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 2:1) to give alkynyl imine 4o (310 mg, 22%).
(Z)-3-(2-Bromophenyl)-N,1-bis(4-methoxyphenyl)prop-2-yn-1-imine (4o)
Yellow solid; mp 138–140 °C; 1H NMR (400 MHz, CDCl3) δ 8.29–8.26
(m, 2H), 7.59–7.57 (m, 1H), 7.34–7.32 (m, 1H), 7.28–7.19
(m, 4H), 7.00–6.92 (m, 4H), 3.88 (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
162.0, 157.3, 147.6, 144.6, 134.5, 132.6, 130.7, 130.4, 129.8, 127.1,
125.8, 124.0, 122.9, 113.8, 113.7, 94.6, 87.4, 55.5, 55.4; IR (KBr)
3062, 2931, 2836, 2209, 1604, 1556, 1511, 1503, 1468, 1322, 1302,
1291, 1249, 1168, 1033, 1022, 856, 844, 821, 753 cm–1; HRMS (EI): calcd for C23H18BrNO2 (M)+ 419.0521, found 419.0521.
In a 300 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed alkynyl aldehyde S6(31) (1.91 g, 9.10 mmol) and MgSO4 (19.7 g, 16.4 mmol), and to it were added DCM (70 mL) and aniline (1.02 mL, 10.9 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was through a Celite pad. The Celite pad was washed with DCM (20 mL). The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/Et3N = 10:1) to give alkynyl imine 4p (1.88 g, 74%, dr = 9:1).
3-(2-Bromophenyl)-N-phenylprop-2-yn-1-imine (4p)
Yellow solid; mp 60–62 °C; 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 0.9H),
7.93 (s, 0.1H), 7.64–7.62 (m, 1.8H), 7.55–7.53 (m, 0.2H),
7.41–7.18 (m, 7H); 13C{1H} NMR (125 MHz,
CDCl3) δ 150.9, 150.7, 143.4, 141.7, 134.4, 134.3,
132.6, 132.6, 131.0, 130.9, 129.2, 128.7, 127.3, 127.2, 127.1, 126.1,
126.1, 125.6, 123.7, 123.5, 120.9, 120.8, 94.8, 92.6, 91.2, 87.2;
IR (KBr) 3125, 3056, 2925, 2875, 2206, 1571, 1481, 1468, 1450, 1437,
1427, 1343, 1200, 1160, 1057, 1026, 1015, 946, 906, 852, 757 cm–1; HRMS (EI): calcd for C15H10BrN (M)+ 282.9997, found 282.9994.
In a 100 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed S7(32) (1.34 g, 3.72 mmol) and Et2O (15 mL), and to it was added nBuLi (4.7 mL, 7.44 mmol, 1.6 M in hexane) at −78 °C. The mixture was stirred at −78 °C for 1.5 h and then stirred at −40 °C for 1.5 h. DMF (544 mg, 7.44 mmol) was added at −40 °C. The mixture was stirred at −40 °C for 30 min and then warmed up to room temperature. Saturated aqueous K2HPO4 solution (15 mL) was added to quench the reaction. The mixture was extracted with Et2O (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/Et3N = 10:1) to give alkynyl aldehyde S8 (403 mg, 48%).
3-(2-Bromo-5-fluorophenyl)propiolaldehyde (S8)
Red oil; 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.62–7.60 (m, 1H), 7.34–7.31 (m, 1H), 7.10–7.06 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.2, 161.1 (d, J = 248.7 Hz), 134.3 (d, J = 7.2 Hz), 123.4 (d, J = 8.5 Hz), 121.6 (d, J = 24.1 Hz), 121.4 (d, J = 3.6 Hz), 120.0 (d, J = 22.9 Hz), 91.5, 90.7 (d, J = 2.4 Hz), 93.3 (d, J = 3.62 Hz), 91.8, 91.1 (d, J = 2.4 Hz), 87.7; 19F NMR (470 MHz, CDCl3) δ −113.4 (s, 1F); IR (neat) 3084, 2863, 2202, 1665, 1573, 1462, 1399, 1291, 1267, 1172, 1116, 1047, 1008, 891, 881, 816, 716 cm–1; HRMS (EI): calcd for C15H9BrFN (M)+ 225.9430, found 225.9425.
In a 50 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed alkynyl aldehyde S8 (332 mg, 1.46 mmol) and MgSO4 (303 mg, 2.52 mmol), and to it were added DCM (10 mL) and aniline (163 mg, 1.76 mmol) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was filtered through a Celite pad. The Celite pad was washed with DCM (15 mL). The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/Et3N = 10:1) to give alkynyl imine 4q (424 mg, 96%, dr = 9:1).
3-(2-Bromo-5-fluorophenyl)-N-phenylprop-2-yn-1-imine (4q)
Yellow solid; mp 70–72 °C; 1H NMR (500 MHz, CDCl3) δ 7.98 (s, 0.9H),
7.91 (s, 0.1H), 7.59–7.56 (m, 0.9H), 7.49–7.47 (m, 0.1H),
7.41–7.36 (m, 2H), 7.34–7.15 (m, 4H), 7.02–6.98
(m, 0.9H), 6.96–6.92 (m, 0.1H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.2 (d, J = 248.7 Hz), 161.1 (d, J = 248.7 Hz), 150.7, 150.6,
142.9, 141.3, 134.0 (d, J = 7.2 Hz), 129.3, 128.7,
127.6, 125.8, 125.2 (d, J = 9.7 Hz), 124.9 (d, J = 9.7 Hz), 120.9 (d, J = 24.1 Hz), 120.9,
120.7, 120.6, 118.7 (d, J = 21.7 Hz), 118.6 (d, J = 22.9 Hz), 93.3 (d, J = 3.6 Hz), 91.8,
91.1 (d, J = 2.4 Hz), 87.7; 19F NMR (470
MHz, CDCl3) δ −114.1 (s, 0.9F), −114.2
(s, 0.1F); IR (KBr) 3053, 2957, 2871, 2204, 1595, 1574, 1485, 1472,
1460, 1405, 1299, 1262, 1174, 1157, 1129, 1058, 1023, 869, 840, 822,
756 cm–1; HRMS (EI): calcd for C15H9BrFN (M)+ 300.9902, found 300.9896.
In a 50 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed nitrone S3a (671 mg, 3.40 mmol), CuI (64.8 mg, 0.340 mmol), DPPE (136 mg, 0.340 mmol), and K2CO3 (517 mg, 3.70 mmol), and to it were added DMF (10 mL), H2O (0.13 mL, 6.80 mmol), and 1-bromo-2-ethynylbenzene S2b(32) (674 mg, 3.40 mmol) in DMF (4 mL) at room temperature. The mixture was stirred at 80 °C for 4 h. DCM (5 mL) and H2O (20 mL) were added to quench the reaction. The mixture was extracted with Et2O (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/toluene = 2:1) to give alkynyl imine 4r (662 mg, 51%).
(Z)-3-(2-Bromo-5-fluorophenyl)-N,1-diphenylprop-2-yn-1-imine (4r)
Yellow solid; mp 98–100 °C; 1H NMR (500 MHz, CDCl3) δ 8.32–8.30 (m, 2H), 7.55–7.49 (m, 4H), 7.43–7.40 (m, 2H), 7.22–7.15 (m, 3H), 6.97–6.90 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.1 (d, J = 248.7 Hz), 151.6, 149.5, 136.8, 133.9 (d, J = 8.5 Hz), 131.4, 128.6, 128.5, 128.2, 125.2 (d, J = 9.7 Hz), 125.0, 121.2 (d, J = 24.1 Hz), 120.6, 120.4 (d, J = 3.6 Hz), 118.5 (d, J = 22.9 Hz), 94.0, 87.4; 19F NMR (470 MHz, CDCl3) δ −114.2 (s, 1F); IR (KBr) 3059, 2206, 1954, 1898, 1571, 1548, 1471, 1458, 1448, 1401, 1319, 1271, 1256, 1208, 1179, 1173, 1116, 1049, 1016, 865, 822, 798, 769, 755, 690 cm–1; HRMS (EI): calcd for C21H13BrFN (M)+ 377.0215, found 377.0219.
Experimental Procedure for the Optimization of Conjugate Addition Reaction (Table 1)
Table 1, entry 1: In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5a (84.8 mg, 0.25 mmol) and 1,4-dioxane (2.0 mL), and to it was added KHMDS (0.40 mL, 0.20 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added a solution of alkynyl imine 4a (36.0 mg, 0.10 mmol) in 1,4-dioxane (2.0 mL). The mixture was stirred under reflux for 10 h and cooled to room temperature, and then to it was added brine (10 mL). The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 4:1) to give 3-amino-2-pyridone 6 (41.2 mg, 76%).
4-(2-Bromophenyl)-3-((diphenylmethylene)amino)-1,6-diphenylpyridin-2(1H)-one (6)
Yellow solid; mp 179–181 °C; 1H NMR (400 MHz, CDCl3) δ 7.62–7.53 (m, 3H), 7.39–7.01 (m, 21H), 6.15 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.5, 141.9, 139.6, 139.0, 138.8, 138.1, 137.7, 137.3, 135.8, 133.1, 132.9, 132.5, 131.6, 130.7, 130.2, 129.8, 129.5, 129.3, 129.1, 128.6, 128.4, 127.9, 127.8, 127.0, 122.7, 110.6; IR (KBr) 3054, 2922, 2855, 1725, 1652, 1598, 1489, 1447, 1365, 1317, 1271, 1220, 1147, 1089, 1081, 1027, 959, 918, 843, 759, 695 cm–1; HRMS (EI): calcd for (M)+ 580.1150, found 580.1176.
Table 1, entry 4: In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (46.0 mg, 0.20 mmol) and 1,4-dioxane (4.0 mL), and to it was added KHMDS (0.20 mL, 0.10 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 15 min, and then to it was added alkynyl imine 4a (36.0 mg, 0.10 mmol). The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added brine (10 mL). The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc/Et3N = 4:1:1, three times) to give 3-amino-2-pyridone 3 (41.2 mg, 76%).
Ethyl (E)-4-(2-Bromophenyl)-5-(((dimethylamino)methylene)amino)-6-oxo-1,2-diphenyl-1,6-dihydropyridine-3-carboxylate (3)
Yellow solid; mp 133–135 °C; 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.30–7.01 (m, 13H), 3.63–3.55 (m, 2H), 2.86 (brs, 3H), 2.63 (brs, 3H), 0.63 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.5, 160.7, 155.0, 139.4, 139.4, 138.9, 136.4, 135.8, 133.9, 131.8, 130.4, 130.2, 129.9, 129.1, 129.0, 128.7, 128.7, 128.4, 128.2, 127.8, 127.5, 127.3, 126.5, 124.1, 116.3, 60.7, 39.9, 33.0, 13.12; IR (KBr) 3050, 2986, 2923, 1715, 1653, 1614, 1492, 1474, 1427, 1416, 1386, 1308, 1243, 1148, 1103, 1021, 959, 763, 750, 728, 697, 646, 568 cm–1; HRMS (EI): calcd for (M)+ 543.1158, found 543.1162.
Experimental Procedure for the Substrate Scope in the Conjugate Addition Reaction (Scheme 3)
Procedure for the Scaling-Up Reaction
In a 100 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (461 mg, 2.00 mmol) and 1,4-dioxane (40 mL), and to it was added KHMDS (2.0 mL, 1.00 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4a (360 mg, 1.00 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (10 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (20 mL) was added to quench the reaction. The mixture was extracted with DCM (40 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 1:1) to give 3-amino-2-pyridone 2a (352 mg, 72%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-1,2-diphenyl-1,6-dihydropyridine-3-carboxylate (2a)
White solid; mp 203–204 °C; 1H NMR (400 MHz, CDCl3) δ 7.71–7.69 (m, 1H), 7.42–7.36 (m, 2H), 7.27–7.07 (m, 11 H), 4.26 (s, 2H), 3.58 (q, J = 7.1 Hz, 2H), 0.60 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 157.8, 138.5, 136.4, 135.8, 134.2, 133.9, 133.1, 131.0, 130.5, 129.8, 129.0, 128.7, 128.7, 128.1, 128.0, 127.9, 127.4, 127.4, 123.7, 121.3, 115.6, 60.6, 13.1; IR (KBr) 3485, 3375, 3057, 2979, 2899, 1715, 1651, 1608, 1592, 1524, 1490, 1472, 1455, 1443, 1376, 1320, 1244, 1185, 1137, 1082, 1073, 1046, 1025, 1007, 876, 830, 756, 724, 704, 695 cm–1; HRMS (EI): calcd for C26H21BrN2O3 (M)+ 488.0736, found 488.0746.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (230 mg, 1.00 mmol) and 1,4-dioxane (20 mL), and to it was added KHMDS (1.0 mL, 0.500 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4b (187 mg, 0.500 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and then cooled to room temperature. The mixture was added 1 M aqueous H2SO4 solution (5 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2b (166 mg, 66%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-2-phenyl-1-(p-tolyl)-1,6-dihydropyridine-3-carboxylate (2b)
White solid; mp 203–204 °C; 1H NMR (400 MHz, CDCl3) δ 7.71–7.69 (m, 1H), 7.42–7.35 (m, 2H), 7.28–7.23 (m, 1H), 7.13–6.94 (m, 9H), 4.25 (s, 2H), 3.58 (q, J = 7.2, 2H), 2.25 (s, 3H), 0.61 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 157.7, 137.7, 136.3, 135.8, 135.7, 134.0, 133.9, 133.0, 130.9, 130.3, 129.7, 129.2, 128.5, 127.9, 127.8, 127.3, 127.2, 123.6, 121.1, 115.4, 60.5, 20.9, 13.0; IR (KBr) 3469, 3368, 3055, 2980, 2918, 1710, 1650, 1594, 1587, 1509, 1471, 1396, 1378, 1318, 1243, 1186, 1092, 1048, 1024, 756, 700 cm–1; HRMS (EI): calcd for C27H23BrN2O3 (M)+ 502.0892, found 502.0911.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (138 mg, 0.600 mmol) and 1,4-dioxane (12 mL), and to it was added KHMDS (0.60 mL, 0.300 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4c (112 mg, 0.300 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (3 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (6 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2, DCM/EtOAc = 40:1) to give 3-amino-2-pyridone 2c (107 mg, 71%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-2-phenyl-1-(m-tolyl)-1,6-dihydropyridine-3-carboxylate (2c)
White solid; mp 168–170 °C; 1H NMR (400 MHz, CDCl3) δ 7.72–7.70 (m, 1H), 7.43–7.35 (m, 2H), 7.28–7.24 (m, 1H), 7.15–7.09 (m, 6H), 6.99–6.86 (m, 3H), 4.25 (s, 2H), 3.59 (q, J = 7.1 Hz, 2H), 2.25 (s, 1.5H), 2.22(s, 1.5H), 0.61 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 157.8, 138.7, 138.6, 138.3, 136.4, 135.9, 134.2, 133.9, 133.1, 131.0, 130.4, 129.8, 129.5, 128.8, 128.5, 128.5, 128.1, 127.9, 127.3, 125.9, 123.7, 121.4, 115.5, 60.6, 21.1, 21.0, 13.1; IR (KBr) 3469, 3366, 3058, 2976, 2924, 2859, 1710, 1652, 1633, 1585, 1525, 1489, 1473, 1437, 1396, 1382, 1322, 1247, 1207, 1180, 1085, 1047, 1033, 1025, 756, 719, 700, 691 cm–1; HRMS (EI): calcd for C27H23BrN2O3 (M)+ 502.0892, found 502.0867.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (230 mg, 1.00 mmol) and 1,4-dioxane (20 mL), and to it was added KHMDS (1.0 mL, 0.500 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4d (187 mg, 0.500 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (5 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2d (73.8 mg, 33%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-2-phenyl-1-(o-tolyl)-1,6-dihydropyridine-3-carboxylate (2d)
White solid; mp 185–187 °C; 1H NMR (400 MHz, CDCl3) δ 7.72–7.70 (m, 1H), 7.43–7.37 (m, 2H), 7.28–6.97 (m, 10H), 4.26–4.25 (m, 2H), 3.59 (q, J = 7.1 Hz, 2H), 2.18 (s, 1.9H), 2,12 (s, 1.1H), 0.62–0.59 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 166.3, 157.2, 157.1, 137.6, 136.4, 135.8, 135.7, 135.4, 135.1, 134.2, 134.1, 133.6, 133.5, 133.1, 131.0, 130.8, 130.6, 130.5, 129.8, 129.2, 129.2, 129.0, 128.8, 128.5, 128.5, 128.3, 127.9, 127.9, 127.4, 127.3, 127.2, 126.2, 126.2, 123.8, 123.6, 121.5, 121.4, 115.7, 60.6, 17.9, 17.7, 13.1; IR (KBr) 3497, 3381, 3054, 2979, 2928, 1713, 1650, 1586, 1523, 1490, 1471, 1376, 1319, 1245, 1181, 1145, 1086, 1046, 1025, 877, 762, 722 cm–1; HRMS (EI): calcd for C27H23BrN2O3 (M)+ 502.0892, found 502.0903.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (230 mg, 1.00 mmol) and 1,4-dioxane (20 mL), and to it was added KHMDS (1.0 mL, 0.500 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4e (195 mg, 0.500 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (5 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2e (102 mg, 39%).
Ethyl 5-Amino-4-(2-bromophenyl)-1-(4-methoxyphenyl)-6-oxo-2-phenyl-1,6-dihydropyridine-3-carboxylate (2e)
Yellow solid; mp 198–200 °C; 1H NMR (400 MHz, CDCl3) δ 7.72–7,70 (m, 1H), 7.43–7.35 (m, 2H), 7.28–7.24 (m, 1H), 7.12–7.08 (m, 5H), 7.03–6.96 (m, 2H), 6.79–6.73 (m, 2H), 4.25 (s, 2H), 3.73 (s, 3H), 3.59 (q, J = 7.2 Hz, 2H), 0.61 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 158.8, 158.1, 136.5, 136.2, 134.2, 134.1, 133.1, 131.2, 131.0, 130.4, 129.9, 128.1, 127.9, 127.5, 127.5, 123.7, 121.4, 115.5, 114.0, 114.0, 60.7, 55.3, 13.2; IR (KBr) 3476, 3322, 3054, 2978, 2929, 2839, 1725, 1648, 1588, 1511, 1472, 1443, 1395, 1323, 1293, 1248, 1187, 1099, 1045, 1029, 756, 700 cm–1; HRMS (EI): calcd for C27H23BrN2O4 (M)+ 518.0841, found 518.0848.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (92.2 mg, 0.400 mmol) and 1,4-dioxane (8 mL), and to it was added KHMDS (0.40 mL, 0.200 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4f (78.9 mg, 0.200 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (2 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2f (71.3 mg, 68%).
Ethyl 5-Amino-4-(2-bromophenyl)-1-(4-chlorophenyl)-6-oxo-2-phenyl-1,6-dihydropyridine-3-carboxylate (2f)
White solid; mp 161–163 °C; 1H NMR (400 MHz, CDCl3) δ 7.72–7.70 (m, 1H), 7.43–7.35 (m, 2H), 7.29–7.7.20 (m, 4H), 7.17–7.11 (m, 3H), 7.07–7.01 (m, 3H), 4.26 (s, 2H), 3.59 (q, J = 7.2 Hz, 2H), 0.62 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 157.6, 136.9, 136.2, 135.3, 134.2, 133.9, 133.5, 133.1, 130.9, 130.3, 130.3, 129.9, 128.9, 128.3, 127.9, 127.6, 127.6, 123.6, 121.3, 115.8, 60.6, 13.1; IR (KBr) 3469, 3368, 3056, 2982, 2925, 2858, 1707, 1654, 1588, 1523, 1490, 1481, 1442, 1429, 1397, 1389, 1378, 1320, 1243, 1187, 1092, 1047, 1027, 864, 840, 787, 759, 737, 700 cm–1; HRMS (EI): calcd for C26H20BrClN2O3 (M)+ 522.0346, found 522.0361.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (138 mg, 0.600 mmol) and 1,4-dioxane (12 mL), and to it was added KHMDS (0.60 mL, 0.300 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4g (112 mg, 0.300 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (3 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2, DCM/EtOAc = 40:1) to give 3-amino-2-pyridone 2g (114 mg, 75%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-1-phenyl-2-(p-tolyl)-1,6-dihydropyridine-3-carboxylate (2g)
White solid; mp 161–163 °C; 1H NMR (400 MHz, CDCl3) δ 7.71–7.70 (m, 1H), 7.42–7.35 (m, 2H), 7.29–6.89 (m, 10H), 4.24 (s, 2H), 3.60 (q, J = 7.1 Hz, 2H), 2.19 (s, 3H), 0.63 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 157.8, 138.5, 137.9, 136.5, 135.9, 134.0, 133.1, 130.9, 130.9, 130.2, 129.8, 129.0, 128.9, 128.7, 128.7, 128.1, 128.0, 127.9, 123.7, 121.5, 115.6, 60.6, 21.1, 13.1; IR (KBr) 3494, 3379, 3056, 2981, 2926, 1713, 1651, 1587, 1505, 1492, 1472, 1374, 1319, 1247, 1187, 1137, 1045, 1025, 837, 802, 754, 734, 705, 695 cm–1; HRMS (EI): calcd for C27H23BrN2O3 (M)+ 502.0892, found 502.0914.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (138 mg, 0.600 mmol) and 1,4-dioxane (12 mL), and to it was added KHMDS (0.60 mL, 0.300 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4h (112 mg, 0.300 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (3 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2h (117 mg, 77%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-1-phenyl-2-(m-tolyl)-1,6-dihydropyridine-3-carboxylate (2h)
White solid; mp 105–107 °C; 1H NMR (400 MHz, CDCl3) δ 7.72–7.70 (m, 1H), 7.43–7.35 (m, 2H), 7.28–7.17 (m, 4H), 7.13–7.06 (m, 2H), 6.98–6.85 (m, 4H), 4.25 (s, 2H), 3.61 (q, J = 7.1 Hz, 2H), 2.19–2.14 (m, 3H), 0.63 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 157.8, 138.5, 137.1, 137.0, 136.4, 136.0, 134.1, 133.7, 133.1, 131.0, 131.0, 129.8, 128.9,128.8, 128.6, 128.5, 128.0, 127.9, 127.5, 127.3, 127.2, 123.7, 121.4, 115.5,, 60.6, 21.0, 13.1; IR (KBr) 3474, 3364, 3053, 2982, 2927, 1722, 1649, 1590, 1523, 1491, 1472, 1378, 1320, 1244, 1199, 1176, 1133, 1093, 1048, 1025, 865, 822, 748, 692 cm–1; HRMS (EI): calcd for C27H23BrN2O3 (M)+ 502.0892, found 502.0876.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (138 mg, 0.600 mmol) and 1,4-dioxane (12 mL), and to it was added KHMDS (0.60 mL, 0.300 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4i (112 mg, 0.300 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (3 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (6 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2, DCM/EtOAc = 40:1) to give 3-amino-2-pyridone 2i (91.7 mg, 61%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-1-phenyl-2-(o-tolyl)-1,6-dihydropyridine-3-carboxylate (2i)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.71–7.68 (m, 1H), 7.44–7.34 (m, 2H), 7.26–6.99 (m, 8H), 6.95–6.90 (m, 2H), 4.26–4.23 (m, 2H), 3.58–3.54 (m, 2H), 2.21–2.18 (m, 3H), 0.60–0.56 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.7, 165.7, 158.0, 157.9, 138.1, 138.0, 137.5, 137.2, 136.5, 136.4, 135.5, 135.5, 134.1, 134.0, 133.2, 133.2, 133.0, 131.2, 130.9, 130.8, 130.8, 129.7, 129.2, 129.2, 129.1, 129.0, 128.6, 128.6, 128.5, 128.5, 128.4, 128.4, 128.1, 128.1, 127.8, 127.1, 127.0, 124.5, 124.5, 123.6, 121.4, 121.3, 115.0, 60.4, 60.3, 20.0, 19.8, 12.9; IR (neat) 3474, 3362, 3058, 2970, 2857, 1721, 1652, 1589, 1526, 1482, 1384, 1317, 1244, 1180, 1117, 1035, 865, 829, 743, 700 cm–1; HRMS (EI): calcd for C27H23BrN2O3 (M)+ 502.0892, found 502.0867.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (92.2 mg, 0.400 mmol) and 1,4-dioxane (8 mL), and to it was added KHMDS (0.40 mL, 0.200 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4j (78.1 mg, 0.200 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (2 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2j (81.8 mg, 79%).
Ethyl 5-Amino-4-(2-bromophenyl)-2-(4-methoxyphenyl)-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (2j)
Yellow solid; mp 176–178 °C; 1H NMR (400 MHz, CDCl3) δ 7.71–7.69 (m, 1H), 7.42–7.35 (m, 2H), 7.30–7.18 (m, 4H), 7.12–6.97 (m, 4H), 6.62–6.60 (m, 2H), 4.24 (s, 2H), 3.68 (s, 3H), 3.62 (q, J = 7.1 Hz, 2H), 0.66 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 159.1, 157.8, 138.5, 136.4, 135.5, 134.0, 133.1, 131.7, 130.9, 129.8, 128.9, 128.9, 128.8, 128.7, 128.0, 127.9, 126.0, 123.7, 121.4, 115.8, 112.8, 60.6, 55.0, 13.2; IR (KBr) 3453, 3339, 3056, 2982, 2836, 1725, 1703, 1647, 1608, 1598, 1507, 1473, 1381, 1320, 1300, 1250, 1185, 1033, 843, 753, 696 cm–1; HRMS (EI): calcd for C27H23BrN2O4 (M)+ 518.0841, found 518.0864.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (92.2 mg, 0.400 mmol) and 1,4-dioxane (8 mL), and to it was added KHMDS (0.40 mL, 0.200 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4k (78.9 mg, 0.200 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (2 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2k (76.0 mg, 73%).
Ethyl 5-Amino-4-(2-bromophenyl)-2-(4-chlorophenyl)-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (2k)
White solid; mp 177–179 °C; 1H NMR (400 MHz, CDCl3) δ 7.71–7.70 (m, 1H), 7.43–7.21 (m, 6H), 7.11–6.99 (m, 6H), 4.29 (s, 2H), 3.61 (q, J = 7.1 Hz, 2H), 0.66 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 157.7, 138.3, 136.3, 134.6, 134.4, 134.3, 133.2, 132.4, 131.8, 131.0, 130.0, 129.0, 129.0, 128.9, 128.4, 128.0, 127.8, 123.7, 121.1, 115.9, 60.9, 13.2; IR (KBr) 3474, 3365, 3058, 2983, 1704, 1645, 1592, 1523, 1491, 1473, 1394, 1320, 1244, 1187, 1092, 1019, 841, 758, 694 cm–1; HRMS (EI): calcd for C26H20BrClN2O3 (M)+ 522.0346, found 522.0358.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (138 mg, 0.600 mmol) and 1,4-dioxane (12 mL), and to it was added KHMDS (0.60 mL, 0.300 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4l (105 mg, 0.300 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (3 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (6 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2, DCM/EtOAc = 40:1) to give 3-amino-2-pyridone 2l (100 mg, 70%).
Ethyl 5-Amino-4-(2-bromophenyl)-2-(furan-2-yl)-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (2l)
Yellow solid; mp 78–80 °C; 1H NMR (400 MHz, CDCl3) δ 7.72–7.70 (m, 1H), 7.43–7.21 (m, 8H), 7.17–7.16 (m, 1H), 6.14 (dd, J = 1.8, 3.7 Hz, 1H), 6.03–6.02 (m, 1H), 4.40 (s, 2H), 3.77 (q, J = 7.1 Hz, 2H), 0.82 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.9, 157.4, 145.0, 142.7, 138.4, 135.9, 135.6, 133.1, 131.0, 130.0, 128.8, 128.4, 128.2, 128.2, 127.9, 125.2, 123.7, 120.3, 117.7, 113.0, 110.7, 61.0, 13.4; IR (KBr) 3496, 3380, 3133, 3060, 2980, 2927, 1715, 1655, 1617, 1589, 1490, 1471, 1379, 1369, 1324, 1247, 1190, 1135, 1072, 1049, 1027, 1004, 941, 884, 750, 696 cm–1; HRMS (EI): calcd for C24H19BrN2O4 (M)+ 478.0528, found 478.0535.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (230 mg, 1.00 mmol) and 1,4-dioxane (20 mL), and to it was added KHMDS (1.0 mL, 0.500 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4m (183 mg, 0.500 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (5 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2m (145 mg, 59%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-1-phenyl-2-(thiophen-2-yl)-1,6-dihydropyridine-3-carboxylate (2m)
White solid; mp 82–83 °C; 1H NMR (400 MHz, CDCl3) δ 7.72–7.70 (m, 1H), 7.43–7.16 (m, 9H), 6.85–6.84 (m, 1H), 6.74 (dd, J = 3.66, 5.04, 1H), 4.36 (s, 2H), 3.68 (q, J = 7.1 Hz, 2H), 0.73 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 157.7, 138.4, 136.0, 135.2, 134.1, 133.2, 131.1, 130.9, 130.0, 128.9, 128.8, 128.8, 128.4, 128.0, 127.7, 125.9, 123.7, 120.6, 118.2, 60.9, 13.3; IR (KBr) 3493, 3376, 3097, 2978, 1713, 1650, 1578, 1491, 1471, 1374, 1321, 1245, 1226, 1201, 1182, 1123, 1073, 1024, 915, 852, 733 cm–1; HRMS (EI): calcd for C24H19BrN2O3S (M)+ 494.0300, found 494.0275.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (230 mg, 1.00 mmol) and 1,4-dioxane (20 mL), and to it was added KHMDS (1.0 mL, 0.500 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4n (193 mg, 0.500 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (5 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2, DCM/EtOAc = 50:1) to give 3-amino-2-pyridone 2n (177 mg, 69%).
Ethyl (E)-5-Amino-4-(2-bromophenyl)-6-oxo-1-phenyl-2-styryl-1,6-dihydropyridine-3-carboxylate (2n)
White solid; mp 139–141 °C; 1H NMR (400 MHz, CDCl3) δ 7.73–7.71 (m, 1H), 7.52–7.48 (m, 2H), 7.45–7.40 (m, 2H), 7.36–7.17 (m, 7H), 7.09–7.06 (m, 2H), 6.64 (d, J = 16.5, 1H), 6.27 (d, J = 16.5, 1H), 4.27 (s, 2H), 3.85 (q, J = 7.2 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.1, 157.5, 138.3, 136.0, 135.9, 134.8, 134.1, 133.1, 132.3, 131.2, 130.0, 129.5, 128.8, 128.6, 128.5, 128.4, 128.3, 127.9, 126.5, 123.8, 121.4, 120.8, 115.1, 61.2, 13.6; IR (KBr) 3491, 3388, 3031, 2987, 2944, 1722, 1647, 1605, 1597, 1580, 1517, 1490, 1473, 1380, 1322, 1235, 1198, 1071, 1025, 972, 871, 753, 692 cm–1; HRMS (EI): calcd for C28H23BrN2O3 (M)+ 514.0892, found 514.0878.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (230 mg, 1.00 mmol) and 1,4-dioxane (20 mL), and to it was added KHMDS (1.0 mL, 0.500 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4o (218 mg, 0.500 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (5 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2o (98.2 mg, 34%).
Ethyl 5-Amino-4-(2-bromophenyl)-1,2-bis(4-methoxyphenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (2o)
Yellow solid; mp 203–204 °C; 1H NMR (400 MHz, CDCl3) δ 7.71–7.69 (m, 1H), 7.40–7.22 (m, 3H), 7.05–6.95 (m, 4H), 6.80–6.74 (m, 2H), 6.64–6.62 (m, 2H), 4.22 (s, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.61 (q, J = 7.1 Hz, 2H), 0.66 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 159.0, 158.7, 158.1, 136.4, 135.8, 134.0, 133.0, 131.6, 131.2, 130.9, 129.7, 127.8, 126.2, 123.7, 121.3, 115.7, 114.0, 112.9, 60.6, 55.2, 55.0, 13.2; IR (KBr) 3478, 3329, 3173, 3068, 2974, 2928, 2838, 1725, 1647, 1584, 1526, 1511, 1472, 1462, 1442, 1395, 1380, 1320, 1297, 1252, 1185, 1137, 1112, 1031, 844, 836, 800, 757 cm–1; HRMS (EI): calcd for C28H25BrN2O5 (M)+ 548.0947, found 548.0945.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (230 mg, 1.00 mmol) and 1,4-dioxane (20 mL), and to it was added KHMDS (1.0 mL, 0.500 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4p (142 mg, 0.500 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (5 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2p (120 mg, 58%).
Ethyl 5-Amino-4-(2-bromophenyl)-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (2p)
White solid; mp 128–129 °C; 1H NMR (500 MHz, CDCl3) δ 7.82 (s, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.55–7.52 (m, 2H), 7.49–7.41 (m, 4H), 7.29–7.25 (m, 2H), 4.22 (brs, 2H), 4.07–3.97 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.6, 157.5, 140.3, 137.3, 135.1, 132.8, 130.7, 130.0, 129.3, 128.7, 127.9, 126.4, 123.4, 121.7, 111.1, 60.5, 13.6; IR (KBr) 3464, 3357, 3169, 3079, 2980, 1702, 1653, 1589, 1491, 1475, 1369, 1332, 1245, 1178, 1084, 1048, 1022, 846, 784, 759, 725, 697 cm–1; HRMS (EI): calcd for C20H17BrN2O3 (M)+ 412.0423, found 414.0420.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (230 mg, 1.00 mmol) and 1,4-dioxane (20 mL), and to it was added KHMDS (1.0 mL, 0.50 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4q (151 mg, 0.500 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (5 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2) to give 3-amino-2-pyridone 2q (143.3 mg, 69%).
Ethyl 5-Amino-4-(2-bromo-5-fluorophenyl)-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (2q)
White solid; mp 115–117 °C; 1H NMR (500 MHz, CDCl3) δ 7.82 (s, 1H), 7.68–7.64 (m, 1H), 7.56–7.52 (m, 2H), 7.49–7.46 (m, 3H), 7.05–6.99 (m, 2H), 4.25 (s, 2H), 4.08–4.02 (m, 2H), 1.05–1.02 (t, J = 7.1, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.4, 162.1 (d, J = 248.2 Hz), 157.4, 140.3, 139.1 (d, J = 7.7 Hz), 135.1, 134.2 (d, J = 7.7 Hz), 130.9, 129.4, 128.9, 126.4, 120.4, 117.9 (d, J = 3.8 Hz), 117.3 (d, J = 23.0 Hz), 116.6 (d, J = 22.0 Hz), 110.7, 60.7, 13.7; 19F NMR (470 MHz, CDCl3) δ −113.84 (s, 1F); IR (KBr) 3481, 3359, 3064, 2985, 2900, 1716, 1654, 1586, 1518, 1448, 1364, 1323, 1240, 1185, 1045, 876, 785, 726, 697 cm–1; HRMS (EI): calcd for C20H16BrFN2O3 (M)+ 430.0328, found 430.0328.
Procedure for the Scaling-Up Reaction
In a 100 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed diethyl 2-aminomalonate 5b (461 mg, 2.00 mmol) and 1,4-dioxane (40 mL), and to it was added KHMDS (2.0 mL, 1.00 mmol, 0.50 M in toluene) at room temperature. The reaction mixture was stirred at room temperature for 10 min, and then to it was added alkynyl imine 4r (378 mg, 1.00 mmol) at 100 °C. The mixture was stirred under reflux for 1.5 h and cooled to room temperature, and then to it was added 1 M aqueous H2SO4 solution (10 mL). The mixture was stirred under reflux for 6 h and then cooled to room temperature. Saturated aqueous NaHCO3 solution (20 mL) was added to quench the reaction. The mixture was extracted with DCM (40 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (hexane/EtOAc = 3:2, DCM/EtOAc = 50:1) to give 3-amino-2-pyridone 2r (392 mg, 77%).
Ethyl 5-Amino-4-(2-bromo-5-fluorophenyl)-6-oxo-1,2-diphenyl-1,6-dihydropyridine-3-carboxylate (2r)
White solid; mp 128–129 °C; 1H NMR (500 MHz, CDCl3) δ 7.67–7.64 (m, 1H), 7.26–7.06 (m, 11H), 7.01–6.97 (m, 1H), 4.30 (s, 2H), 3.62 (q, J = 7.1 Hz, 2H), 0.63 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.0, 161.8 (d, J = 248.7 Hz), 157.6, 138.2, 138.1, 136.0, 134.4 (d, J = 8.5 Hz), 134.1, 133.7, 130.3, 130.3, 128.8, 128.6, 128.0, 128.0, 127.4, 127.3, 119.9, 118.0 (d, J = 22.9 Hz), 118.0 (d, J = 4.2 Hz), 117.0 (d, J = 22.9 Hz), 114.8, 60.6, 13.0; 19F NMR (470 MHz, CDCl3) δ −113.50 (s, 1F); IR (KBr) 3477, 3362, 3060, 2986, 1721, 1654, 1589, 1530, 1466, 1388, 1318, 1246, 1181, 1037, 958, 872, 700 cm–1; HRMS (EI): calcd for C26H20BrFN2O3 (M)+ 506.0641, found 506.0645.
Experimental Procedure for the Substrate Scope in the Intramolecular Amination (Scheme 5)
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2a (48.9 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (5 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1a (33.1 mg, 83%).
Ethyl 1-Oxo-2,3-diphenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1a)
White solid; mp 292–293 °C; 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.43–7.14 (m, 13H), 4.05 (q, J = 7.1 Hz, 2H), 0.86 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 156.1, 140.1, 139.8, 138.5, 134.6, 130.5, 129.7, 128.7, 128.2, 128.1, 127.5, 127.0, 122.9, 11.4, 120.7, 120.5, 112.7, 110.8, 61.2, 13.5; IR (KBr) 3173, 2982, 2880, 1727, 1653, 1580, 1555, 1490, 1444, 1399, 1391, 1383, 1338, 1311, 1245, 1157, 1145, 1115, 1039, 860, 768, 745, 702 cm–1; HRMS (EI): calcd for C26H20N2O3 (M)+ 408.1474, found 408.1474.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2b (50.3 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1b (34.8 mg, 82%).
Ethyl 1-Oxo-3-phenyl-2-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1b)
White solid; mp > 300 °C; 1H NMR (400 MHz, DMSO) δ 12.39 (s, 1H), 7.87 (d, J = 8.0, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.48–7.45 (m, 1H), 7.22–7.16 (m, 6H), 7.11–7.09 (m, 2H), 7.05–7.04 (m, 2H), 3.96 (q, J = 7.1 Hz, 2H), 2.21 (s, 3H), 0.77 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.3, 155.7, 140.2, 137.4, 136.5, 134.9, 130.9, 130.1, 129.4, 128.5, 127.7, 127.2, 127.1, 122.7, 121.2, 120.6, 119.6, 113.3, 109.5, 61.2, 21.1, 13.8; IR (KBr) 3141,2985, 1726, 1653, 1580, 1554, 1508, 1501, 1496, 1445, 1403, 1393, 1384, 1339, 1313, 1246, 1159, 1146, 1112, 1040, 854, 762, 748, 702 cm–1; HRMS (EI): calcd for C27H22N2O3 (M)+ 422.1630, found 422.1648.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2c (107 mg, 0.213 mmol) in degassed 1,4-dioxane (4 mL), and to it were added Pd2(dba)3 (4.9 mg, 0.0053 mmol), SPhos (6.6 mg, 0.016 mmol), and NaOtBu (40.9 mg, 0.426 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to give β-carbolin-1-one 1c (69.8 mg, 78%).
Ethyl 1-Oxo-3-phenyl-2-(m-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1c)
White solid; mp 284–286 °C; 1H NMR (400 MHz, DMSO) δ 12.38 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.23–7.10 (m, 7H), 7.05–6.98 (m, 3H), 3.97 (q, J = 7.1, 2H), 2.18 (s, 3H), 0.77 (t, 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.2, 155.6, 140.2, 140.1, 139.0, 138.1, 134.8, 130.9, 128.8, 128.5, 128.5, 127.7, 127.6, 127.5, 127.2, 127.1, 122.6, 121.1, 120.6, 119.6, 113.3, 109.5, 61.2, 21.1, 13.8; IR (KBr) 3143, 2961, 1721, 1655, 1552, 1453, 1404, 1394, 1314, 1249, 1144, 1105, 1041, 1004, 864, 751, 702 cm–1; HRMS (EI): calcd for C27H22N2O3 (M)+ 422.1630, found 422.1611.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2d (50.3 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.20 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1d (32.6 mg, 77%).
Ethyl 1-Oxo-3-phenyl-2-(o-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1d)
White solid; mp 292–294 °C; 1H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.39–7.36 (m, 1H), 7.25–7.13 (m, 10H), 7.09–7.08 (m, 1H), 4.07–4.02 (m, 2H), 2.11 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.2, 154.9, 140.2, 139.8, 138.2, 136.0, 134.4, 131.5, 130.9, 130.6, 129.0, 128.8, 128.7, 127.8, 127.7, 127.2, 126.5, 122.7, 121.1, 120.7, 119.8, 113.3, 109.9, 61.2, 17.9, 13.8; IR (KBr) 3144, 3069, 2954, 1717, 1649, 1539, 1451, 1390, 1309, 1246, 1138, 1112, 1038, 1002, 871 cm–1; HRMS (EI): calcd for C27H22N2O3 (M)+ 422.1630, found 422.1637.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2e (51.9 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1e (37.4 mg, 85%).
Ethyl 3-(4-Methoxyphenyl)-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1e)
White solid; mp > 300 °C; 1H NMR (400 MHz, DMSO) δ 12.39 (brs, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.48–7.45 (m, 1H), 7.22–7.18 (m, 6H), 7.15–7.12 (m, 2H), 6.78–6.76 (m, 2H), 3.97 (q, J = 7.1 Hz, 2H), 3.67 (s, 3H), 0.77 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.3, 158.7, 155.9, 140.5, 140.2, 135.0, 131.8, 131.4, 130.9, 128.5, 127.8, 127.3, 127.1, 122.7, 121.2, 120.6, 119.6, 114.0, 113.4, 109.5, 61.2, 55.7, 13.8; IR (KBr) 3141, 2948, 2843, 1727, 1649, 1556, 1509, 1452, 1391, 1317, 1308, 1249, 1146, 1039, 831, 768, 746, 703 cm–1; HRMS (EI): calcd for C27H22N2O4 (M)+ 438.1580, found 438.1580.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2f (52.4 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (NH3 dissolved DCM) to give β-carbolin-1-one 1f (26.3 mg, 59% (91% brsm)) and the recovered 3-amino-2-pyridone 2f (18.4 mg, 35%).
Ethyl 3-(4-Chlorophenyl)-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1f)
White solid; mp > 300 °C; 1H NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.49–7.46 (m, 1H), 7.35–7.30 (m, 4H), 7.24–7.19 (m, 6H), 3.98 (q, J = 7.1 Hz, 2H), 0.77 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.1, 155.5, 140.2, 139.9, 138.2, 134.6, 132.8, 132.4, 130.9, 128.8, 128.7, 127.9, 127.2, 127.1, 122.7, 121.1, 120.7, 119.8, 113.4, 109.7, 61.2, 13.8; IR (KBr) 3147, 3000, 1732, 1653, 1553, 1489, 1445, 1401, 1383, 1340, 1313, 1244, 1146, 1090, 1039, 1015, 830, 767, 745, 703 cm–1; HRMS (EI): calcd for C26H19ClN2O3 (M)+ 442.1084, found 442.1083.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2g (50.3 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1g (30.2 mg, 72%).
Ethyl 1-Oxo-2-phenyl-3-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1g)
White solid; mp > 300 °C; 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.44–7.38 (m, 2H), 7.33–7.27 (m, 3H), 7.23–7.20 (m, 1H), 7.14–7.13 (m, 2H), 7.05–7.03 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 2.25 (s, 3H), 0.90 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.5, 156.1, 139.9, 138.5, 138.0, 131.5, 130.3, 129.6, 128.7, 128.2, 128.0, 127.0, 126.9, 122.9, 121.4, 120.8, 120.5, 112.6, 110.8, 61.2, 21.2, 13.5; IR (KBr) 3203, 2986, 1711, 1653, 1550, 1496, 1460, 1390, 1308, 1241, 1145, 1112, 1033, 747, 702 cm–1; HRMS (EI): calcd for C27H22N2O3 (M)+ 422.1630, found 422.1613.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2h (50.3 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1h (30.1 mg, 71%).
Ethyl 1-Oxo-2-phenyl-3-(m-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1h)
White solid; mp 248–250 °C; 1H NMR (400 MHz, DMSO) δ 12.39 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.49–7.45 (m, 1H), 7.26–7.19 (m, 6H), 7.06–6.97 (m, 4H), 4.02–3.97 (m, 2H),2.15 (s, 3H), 0.79 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.2, 155.6, 140.2, 140.1, 139.1, 136.7, 134.6, 131.4, 130.4, 129.0, 128.7, 128.7, 128.2, 128.0, 127.6, 127.1, 127.1, 122.6, 121.1, 120.6, 119.7, 113.3, 109.5, 61.1, 21.2, 13.7; IR (KBr) 3177, 2987, 1716, 1649, 1547, 1496, 1455, 1391, 1309, 1249, 1145, 1038, 1004, 749 cm–1; HRMS (EI): calcd for C27H22N2O3 (M)+ 422.1630, found 422.1613.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2i (91.7 mg, 0.182 mmol) in degassed 1,4-dioxane (4 mL), and to it were added Pd2(dba)3 (4.2 mg, 0.0046 mmol), SPhos (5.6 mg, 0.014 mmol), and NaOtBu (35.0 mg, 0.364 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to give β-carbolin-1-one 1i (55.6 mg, 69%).
Ethyl 1-Oxo-2-phenyl-3-(o-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1i)
White solid; mp 259–261 °C; 1H NMR (400 MHz, CDCl3) δ 11.32 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.40–7.27 (m, 6H), 7.21–7.18 (m, 1H), 7.16–7.14 (m, 1H), 7.10–7.07 (m, 2H), 7.02–6.97 (m, 2H), 4.07–4.01 (m, 2H), 2.17 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.0, 156.4, 140.2, 139.4, 138.2, 137.4, 133.9, 131.3, 129.9, 129.4, 128.8, 128.5, 128.4, 128.3, 128.0, 127.1, 127.0, 124.7, 123.0, 121.4, 120.9, 120.4, 112.8, 110.7, 61.1, 20.1, 13.4; IR (KBr) 3220, 3061, 2985, 1731, 1653, 1646, 1553, 1490, 1449, 1402, 1390, 1379, 1337, 1309, 1241, 1155, 1144, 1112, 1035, 873, 759, 735, 695 cm–1; HRMS (EI): calcd for C27H22N2O3 (M)+ 422.1630, found 422.1638.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2j (51.9 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg,0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM/iPrOH = 10:2 (12 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by column chromatography on silica gel (DCM/MeOH = 20:1) to give β-carbolin-1-one 1j (40.6 mg, 93%).
Ethyl 3-(4-Methoxyphenyl)-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1j)
White solid; mp > 300 °C; 1H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.61–7.59 (m, 1H), 7.48–7.45 (m, 1H), 7.30–7.19 (m, 6H), 7.12–7.09 (m, 2H), 6.74–6.71 (m, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H), 0.84 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.4, 159.3, 155.7, 140.2, 139.9, 139.3, 132.3, 130.5, 128.9, 128.2, 127.2, 127.2, 127.0, 122.6, 121.2, 120.7, 119.7, 113.4, 113.2, 109.9, 61.2, 55.5, 14.0; IR (KBr) 3175, 2925, 2857, 1708, 1653, 1507, 1462, 1391, 1309, 1249, 1179, 1110, 1039, 746 cm–1; HRMS (EI): calcd for C27H22N2O4 (M)+ 438.1580, found 438.1589.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2k (52.4 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1k (37.8 mg, 84%).
Ethyl 3-(4-Chlorophenyl)-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1k)
White solid; mp > 300 °C; 1H NMR (400 MHz, DMSO) δ 12.45 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.49–7.46 (m, 1H), 7.30–7.19 (m, 10H), 4.03 (q, J = 7.1 Hz, 2H), 0.83 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.0, 155.6, 140.2, 139.0, 139.0, 133.8, 133.4, 132.8, 130.5, 129.0, 128.4, 127.8, 127.4, 127.2, 122.8, 121.2, 120.7, 119.6, 113.4, 109.7, 61.3, 13.8; IR (KBr) 3175, 2994, 1710, 1653, 1538, 1489, 1463, 1397, 1337, 1308, 1250, 1241, 1169, 1146, 1113, 1090, 1038, 754, 705 cm–1; HRMS (EI): calcd for C26H19ClN2O3 (M)+ 442.1084, found 442.1082.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2l (100 mg, 0.209 mmol) in degassed 1,4-dioxane (4 mL), and to it were added Pd2(dba)3 (4.8 mg, 0.0052 mmol), SPhos (6.5 mg, 0.016 mmol), and NaOtBu (40.2 mg, 0.418 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to give β-carbolin-1-one 1l (66.4 mg, 80%).
Ethyl 3-(Furan-2-yl)-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1l)
White solid; mp 271–272 °C; 1H NMR (400 MHz, DMSO) δ 7.92 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.52–7.48 (m, 2H), 7.41–7.34 (m, 3H), 7.30–7.23 (m, 3H), 6.32 (dd, J = 1.7, 3.4 Hz, 1H), 6.17 (d, J = 3.4 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 166.9, 155.4, 145.5, 144.2, 140.2, 138.9, 129.8, 129.6, 129.1, 128.7, 128.1, 127.4, 122.7, 121.2, 121.0, 119.1, 113.8, 113.5, 112.0, 111.4, 61.7, 14.3; IR (KBr) 3168, 2985, 2945, 2891, 1720, 1649, 1589, 1539, 1530, 1489, 1453, 1382, 1335, 1308, 1240, 1176, 1144, 1108, 1041, 1006, 962, 925, 876, 834, 754, 693 cm–1; HRMS (EI): calcd for C24H18N2O4 (M)+ 398.1267, found 398.1276.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2m (49.5 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1m (31.5 mg, 76%).
Ethyl 1-Oxo-2-phenyl-3-(thiophen-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1m)
White solid; mp 291–293 °C; 1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 1.2, 4.6 Hz, 1H), 7.50–7.47 (m, 1H), 7.34–7.21 (m, 6H), 6.96–6.95 (m, 1H), 6.86 (m, 1H), 4.09 (q, J = 7.0 Hz, 2H), 0.93 (t, J = 7.0 Hz, 3H),; 13C{1H} NMR (100 MHz, DMSO) δ 167.1, 155.5, 140.2, 139.0, 134.5, 132.3, 131.8, 130.2, 129.8, 129.0, 128.6, 127.8, 127.3, 126.6, 122.4, 121.0, 120.9, 119.2, 113.5, 112.0, 61.6, 14.0; IR (KBr) 3166, 2984, 2935, 2889, 1712, 1652, 1554, 1523, 1489, 1469, 1382, 1332, 1305, 1240, 1162, 1141, 1105, 1034, 997, 851, 780, 754, 720, 692 cm–1; HRMS (EI): calcd for C24H18N2O3S (M)+ 414.1038, found 414.1033.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2n (92.4 mg, 0.179 mmol) in degassed 1,4-dioxane (4 mL), and to it were added Pd2(dba)3 (4.1 mg, 0.0045 mmol), SPhos (5.5 mg, 0.013 mmol), and NaOtBu (34.4 mg, 0.358 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to give β-carbolin-1-one 1n (52.8 mg, 68%).
Ethyl (E)-1-Oxo-2-phenyl-3-styryl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1n)
White solid; mp 257–258 °C; 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.61–7.51 (m, 3H), 7.41–7.37 (m, 3H), 7.29–7.16 (m, 7H), 6.8 (d, J = 16.0 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.2, 156.0, 140.2, 138.3, 136.5, 136.0, 135.4, 129.5, 129.2, 128.9, 128.7, 128.6, 127.0, 126.9, 126.7, 122.4, 121.9, 121.3, 120.9, 120.5, 112.9, 110.1, 61.8, 14.1; IR (KBr) 3175, 3068, 2985, 1712, 1647, 1550, 1490, 1470, 1452, 1401, 1376, 1308, 1239, 1186, 1136, 1113, 1029, 959, 913, 876, 750, 693 cm–1; HRMS (EI): calcd for C28H22N2O3 (M)+ 434.1630, found 434.1628.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2o (54.9 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1o (31.6 mg, 67%).
Ethyl 2,3-Bis(4-methoxyphenyl)-1-oxo-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1o)
White solid; mp 263–265 °C; 1H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.46 (m, 1H), 7.21–7.19 (m, 1H), 7.13–7.09 (m, 4H), 6.78 (d, 9.2 Hz, 2H), 6.73 (d, J = 9.2 Hz, 2H), 4.00 (q, J = 7.3 Hz, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 0.83 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 167.4, 159.2, 158.7, 156.0, 140.2, 132.2, 131.9, 131.4, 127.2, 127.2, 127.1, 122.6, 121.1, 120.6, 119.7, 114.0, 113.4, 113.2, 109.8, 61.2, 55.7, 55.5, 14.0; IR (KBr) 3165, 2960, 2840, 1705, 1649, 1608, 1509, 1459, 1390, 1337, 1313, 1248, 1179, 1145, 1111, 1031, 831, 802, 756 cm–1; HRMS (EI): calcd for C28H24N2O5 (M)+ 468.1685, found 468.1673.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2p (41.3 mg, 0.100 mmol) in degassed 1,4-dioxane (2 mL), and to it were added Pd2(dba)3 (2.3 mg, 0.0025 mmol), SPhos (3.1 mg, 0.0075 mmol), and NaOtBu (19.2 mg, 0.200 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (10 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (ammonia solution in DCM) to give β-carbolin-1-one 1p (24.7 mg, 74%) as a white solid.
Ethyl 1-Oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1p)
White solid; mp 280–282 °C; 1H NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 8.78 (d, 8.24, 1H), 8.04 (s, 1H), 7.61–7.51 (m, 6H), 7.49–7.44 (m, 1H), 7.25–7.21 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 165.4, 155.3, 140.8, 140.4, 135.7, 129.8, 129.1, 128.0, 127.8, 127.2, 126.0, 121.8, 120.5, 120.2, 113.0, 107.4, 61.2, 14.7; IR (KBr) 3199, 2987, 1717, 1658, 1651, 1603, 1581, 1560, 1523, 1492, 1416, 1317, 1235, 1168, 1094, 1038, 1011, 942, 873, 785, 755, 722, 707 cm–1; HRMS (EI): calcd for C20H16N2O3 (M)+ 332.1161, found 332.1157.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2q (143 mg, 0.347 mmol) in degassed 1,4-dioxane (7 mL), and to it were added Pd2(dba)3 (8.0 mg, 0.0087 mmol), SPhos (10.7 mg, 0.026 mmol), and NaOtBu (66.7 mg, 0.694 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (30 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to give β-carbolin-1-one 1q (111 mg, 91%).
Ethyl 6-Fluoro-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1q)
White solid; mp > 300 °C; 1H NMR (500 MHz, CDCl3) δ 8.52 (dd, J = 2.9, 10.9 Hz, 1H), 8.05 (s, 1H), 7.62–7.52 (m, 6H), 7.39–7.25 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.3, 157.2 (d, J = 231.8), 155.3, 140.7, 137.1, 135.9, 129.8, 129.4, 129.2, 127.8, 121.8 (d, J = 10.9 Hz), 120.0 (d, J = 4.8 Hz), 116.1 (d, J = 26.6 Hz), 114.3 (d, J = 9.7 Hz), 110.4 (d, J = 24.1 Hz), 107.0, 61.3, 14.7; 19F NMR (470 MHz, CDCl3) δ −122.57 (s, 1F); IR (KBr) 3435, 3205, 2985, 1727, 1667, 1631, 1586, 1566, 1486, 1457, 1444, 1409, 1391, 1365, 1318, 1273, 1235, 1179, 1153, 1116, 1089, 1037, 1005, 979, 876, 805, 70, 747, 721, 698 cm–1; HRMS (EI): calcd for C20H15FN2O3 (M)+ 350.1067, found 350.1058.
Procedure for the Scaling-Up Reaction
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon was placed 3-amino-2-pyridone 2r (330 mg, 0.650 mmol) in degassed 1,4-dioxane (13 mL), and to it were added Pd2(dba)3 (14.9 mg, 0.0163 mmol), SPhos (20.0 mg, 0.0488 mmol), and NaOtBu (125 mg, 1.30 mmol) at room temperature. The mixture was stirred under reflux for 4 h and then cooled to room temperature. Brine (65 mL) was added to quench the reaction. The mixture was extracted with DCM (65 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to give β-carbolin-1-one 1r (227 mg, 82%).
Ethyl 6-Fluoro-1-oxo-2,3-diphenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (1r)
White solid; mp 291–293 °C; 1H NMR (500 MHz, CDCl3) δ 11.19 (s, 1H), 7.73–7.70 (m, 1H), 7.34–7.27 (m, 3H), 7.24–7.21 (m, 1H), 7.18–7.13 (m, 8H), 4.04 (q, J = 7.1 Hz, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 167.1, 157.7 (d, J = 236.7), 156.1, 140.1, 138.3, 136.6, 134.5, 130.5, 129.6, 128.7, 128.3, 128.2, 127.6, 121.6 (d, J = 10.5 Hz), 120.7 (d, J = 4.8 Hz), 116.0 (d, J =26.8 Hz), 113.5 (d, J = 8.6 Hz), 110.5, 108.0 (d, J = 24.9 Hz), 61.3, 13.4; 19F NMR (470 MHz, CDCl3) δ −122.04 (s, 1F); IR (KBr) 3190, 3070, 2986, 2896, 1715, 1655, 1590, 1537, 1492, 1446, 1387, 1314, 1238, 1145, 1103, 1033, 981, 861, 803, 754, 713 cm–1; HRMS (EI): calcd for C26H19FN2O3 (M)+ 426.1380, found 426.1399.
Synthesis of SL651498 and Its Analogue 11 (Scheme 6)
In a 50 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed β-carbolin-1-one 1q (111 mg, 0.318 mmol) and DMF (10 mL). The mixture was stirred at 50 °C until it melted and then cooled to room temperature. NaH (21.7 mg, 0.541 mmol, 60% in oil) was added to it at room temperature. The reaction mixture was stirred at room temperature for 1 h, and then to it was added MeI (113 mg, 0.795 mmol). The reaction mixture was stirred at room temperature for 12 h. H2O (30 mL) was added to quench the reaction. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to N-methyl-β-carbolin-1-one 7 (85.3 mg, 74%).
Ethyl 6-Fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (7)
White solid; mp 203–205 °C; 1H NMR (500 MHz, CDCl3) δ 8.64–8.61 (m, 1H), 8.05 (s, 1H), 7.57–7.54 (m, 2H), 7.50–7.46 (m, 3H), 7.35–7.32 (m, 1H), 7.28–7.24 (m, 1H), 4.43 (q, J = 7.2 Hz, 2H), 4.26 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.0, 157.5 (d, J = 235.4 Hz), 156.2, 140.3, 138.0, 135.0, 129.4, 128.7, 127.5, 127.0, 121.0 (d, J = 4.8 Hz), 120.8 (d, J = 10.9 Hz), 115.9 (d, J = 27.8 Hz), 111.2 (d, J = 25.4 Hz), 110.3 (d, J = 9.7 Hz), 107.6, 61.0, 31.5, 14.3; 19F NMR (470 MHz, CDCl3) δ −122.10 (s, 1F); IR (KBr) 3120, 2976, 2933, 1723, 1668, 1487, 1402, 1414, 1299, 1266, 1247, 1128, 1072, 918, 879, 803, 777, 718, 697 cm–1; HRMS (EI): calcd for C21H17FN2O3 (M)+ 364.1223, found 364.1208.
In a 100 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed N-methyl-β-carbolin-1-one 7 (56.0 mg, 0.154 mmol), 1 M KOH aqueous solution (10 mL), and EtOH (15 mL) at room temperature. The mixture was stirred under reflux for 10 min and then cooled to room temperature. 2 M HCl aqueous solution (30 mL) was added to quench the reaction. The mixture was extracted with DCM (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo to give 4-carboxy-β-carbolin-1-one 9 (49.0 mg, 95%).
6-Fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylic Acid (9)
White solid; mp 293–294 °C; 1H NMR (500 MHz, DMSO) δ 8.66–8.63 (m, 1H), 8.01 (s, 1H), 7.71–7.69 (m, 1H), 7.60–7.51 (m, 5H), 7.45–7.41 (m, 1H), 4.24 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 166.8, 157.3 (d, J = 233.0 Hz), 155.9, 140.8, 138.3, 136.2, 129.7, 129.1, 127.7, 120.9 (d, J = 4.8 Hz), 120.6 (d, J =12.1 Hz), 116.1 (d, J = 26.6 Hz)112.3 (d, J = 8.5 Hz), 110.9 (d, J = 25.4 Hz), 107.4, 32.0; 19F NMR (470 MHz, CDCl3) δ −122.38 (s, 1F); IR (KBr) 3072, 2930, 1668, 1488, 1423, 1293, 1270, 1131, 1070, 914, 788, 778, 698 cm–1; HRMS (EI): calcd for C19H13FN2O3 (M)+ 336.0910, found 336.0899.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed 4-carboxy-β-carbolin-1-one 9 (18.7 mg, 0.0556 mmol) and DCM (3 mL), and to it were added oxalyl chloride (15.5 mg, 0.122 mmol) and DMF (9.4 mg, 0.13 mmol) at room temperature. The mixture was stirred at room temperature for 10 min, and then to it were added pyrrolidine (173 mg, 2.44 mmol) and Et3N (145 mg, 1.43 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. H2O (10 mL) was added. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to give SL651498 (20.7 mg, 96%).
6-Fluoro-9-methyl-2-phenyl-4-(pyrrolidine-1-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (SL651498)
Yellow solid; mp 170–172 °C; 1H NMR (500 MHz, CDCl3) δ 7.60–7.58 (m, 1H), 7.54–7.51 (m, 2H), 7.47–7.43 (m, 4H), 7.32–7.28 (m, 2H), 4.34 (s, 3H), 3.79 (t, J = 6.9 Hz, 2H), 3.41 (t, J = 6.6 Hz, 2H), 2.05–2.00 (m, 2H), 1.92–18.6 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.8, 158.0 (d, J =237.8 Hz), 156.0, 140.5, 137.8, 129.4, 128.5, 127.9, 127.6, 127.1, 120.4 (d, J =10.9), 116.0 (d, J = 26.6), 113.0, 111.2 (d, J =8.5 Hz), 107.1 (d, J = 24.1 Hz), 48.8, 46.1, 31.7, 26.1, 24.6; 19F NMR (470 MHz, CDCl3) δ −121.70 (s, 1F); IR (KBr) 3070, 2956, 2877, 1668, 1624, 1491, 1438, 1302, 1262, 1170, 1078, 943, 895, 850, 795, 763, 740, 699 cm–1; HRMS (EI): calcd for C23H20FN3O2 (M)+ 389.1540, found 389.1552.
In a 100 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed β-carbolin-1-one 1r (213 mg, 0.500 mmol) and DMF (10 mL). NaH (33.6 mg, 0.840 mmol, 60% in oil) was added to it at room temperature. The reaction mixture was stirred at room temperature for 1 h, and then to it was added MeI (179 mg, 1.26 mmol). The reaction mixture was stirred at room temperature for 12 h. H2O (50 mL) was added to quench the reaction. The mixture was extracted with DCM (15 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to N-methyl-β-carbolin-1-one 8 (213 mg, 97%).
Ethyl 6-Fluoro-9-methyl-1-oxo-2,3-diphenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylate (8)
White solid; mp 198–199 °C; 1H NMR (500 MHz, CDCl3) δ 7.72–7.70 (m, 1H), 7.44–7.41 (m, 1H), 7.31–7.13 (m, 9H), 7.09–7.08 (m, 2H), 4.32 (s, 3H), 4.03 (q, J = 7.2 Hz, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 167.2, 157.7 (d, J = 236.6), 156.7, 139.9, 138.4, 138.0, 134.4, 130.3, 129.5, 128.7, 128.2, 128.0, 127.5, 127.1, 120.4 (d, J = 9.7), 120.2 (d, J = 4.8 Hz), 115.9 (d, J = 26.6 Hz), 110.9 (d, J = 8.5 Hz), 109.8, 108.0 (d, J = 25.4 Hz), 61.3, 31.5, 13.4; 19F NMR (470 MHz, CDCl3) δ −121.98 (s, 1F); IR (KBr) 3063, 2986, 2940, 2898, 1720, 1663, 1657, 1553, 1481, 1442, 1399, 1316, 1259, 1248, 1228, 1156, 1135, 1093, 1028, 936, 863, 799, 788, 761, 749, 714, 691 cm–1; HRMS (EI): calcd for C20H15FN2O3 (M)+ 440.1536, found 440.1542.
Batch conditions: In a 300 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, a Dimroth condenser, and an argon balloon were placed N-methyl-β-carbolin-1-one 8 (39.9 mg, 0.0906 mmol), 1 M KOH aqueous solution (40 mL), and EtOH (60 mL) at room temperature. The mixture was stirred under reflux for 48 h and then cooled to room temperature. The mixture was extracted with DCM (100 mL). 2 M HCl aqueous solution (50 mL) was added to the aqueous layer. The mixture was extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo to give 4-carboxy-β-carbolin-1-one 10 (23.3 mg, 62% (95% brsm)) and the recovered N-methyl-β-carbolin-1-one 8 (14.0 mg, 35%).
Microwave conditions: In a microwave reactor vial including a magnetic stirring bar were placed N-methyl-β-carbolin-1-one 8 (17.9 mg, 0.0406 mmol), 1 M KOH aqueous solution (2 mL), and EtOH (3 mL) at room temperature. The vial was placed in a microwave reactor and irradiated at 180 °C for 2 h. The mixture was then cooled to room temperature. 2 M HCl aqueous solution (5 mL) was added to quench the reaction. The mixture was extracted with DCM (5 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo to give 4-carboxy-β-carbolin-1-one 10 (13.6 mg, 81%).
6-Fluoro-9-methyl-1-oxo-2,3-diphenyl-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylic Acid (10)
White solid; mp 299–300 °C; 1H NMR (500 MHz, DMSO) δ 7.83–7.80 (m, 1H), 7.68–7.65 (m, 1H), 7.50–7.46 (m, 1H), 7.25–7.14 (m, 10H), 4.28 (s, 3H); 13C{1H} NMR (100 MHz, DMSO) δ 168.4, 157.5 (d, J = 234.8 Hz), 156.1, 139.2, 139.1, 138.2, 134.5, 131.0, 130.5, 128.8, 128.5, 128.2, 127.7, 127.2, 120.2 (d, J = 10.5), 119.8 (d, J = 4.8 Hz), 116.1 (d, J = 25.9 Hz), 113.1 (d, J = 9.6 Hz), 110.4, 107.1 (d, J = 24.9 Hz), 32.0; 19F NMR (470 MHz, CDCl3) δ −122.35 (s, 1F); IR (KBr) 3068, 2931, 1726, 1644, 1483, 1399, 1308, 1300, 1259, 1219, 1142, 1086, 1029, 933, 852, 796, 748, 741, 695 cm–1; HRMS (EI): calcd for C25H17FN2O3 (M)+ 412.1223, found 412.1227.
In a 30 mL two-neck round-bottom flask equipped with a magnetic stirring bar, a rubber septum, and an argon balloon were placed 4-carboxy-β-carbolin-1-one 10 (10.3 mg, 0.0250 mmol) and DCM (3 mL), and to it were added oxalyl chloride (7.2 mg, 0.056 mmol) and DMF (9.4 mg, 0.13 mmol) at room temperature. The mixture was stirred at 10 min for room temperature, and then to it were added pyrrolidine (173 mg, 2.44 mmol) and Et3N (145 mg, 1.43 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. H2O (10 mL) was added. The mixture was extracted with DCM (5 mL × 3). The combined organic layers were dried over sodium sulfate. The solvents were evaporated in vacuo, and then the residue was purified by preparative TLC on silica gel (DCM/MeOH = 30:1) to SL651498 analogue (11) (11.3 mg, 97%).
6-Fluoro-9-methyl-2,3-diphenyl-4-(pyrrolidine-1-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one (11)
White solid; mp 235–237 °C; 1H NMR (500 MHz, CDCl3) δ 7.61–7.53 (m, 1H), 7.50–7.43 (m, 3H), 7.39–7.35 (m, 1H), 7.32–7.26 (m, 2H), 7.21–7.12 (m, 3H), 7.08–7.00 (m, 1H), 6.96–6.86 (m, 1H), 6.81–6.80 (m, 1H), 4.34 (s, 3H), 3.69–3.62 (m, 1H), 3.26–3.19 (m, 1H), 3.15–3.09 (m, 1H), 3.03–2.97 (m, 1H), 1.87–1.78 (m, 1H), 1.70–1.45 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.6, 158.0 (d, J = 237.8 Hz), 156.8, 138.7, 138.0, 135.7, 133.5, 131.0, 130.1, 129.6, 129.1, 129.0, 128.2, 127.8, 127.4, 127.1, 120.6 (d, J =10.9), 120.1 (d, J = 4.8 Hz), 115.9 (d, J = 26.6), 113.2, 111.2 (d, J = 9.7 Hz), 106.7 (d, J = 24.1 Hz), 47.5, 45.3, 31.6, 25.6, 24.4; 19F NMR (470 MHz, CDCl3) δ −121.82 (s, 1F); IR (KBr) 3059, 2973, 2937, 2872, 1651, 1558, 1480, 1437, 1308, 1285, 1436, 1308, 1285, 1254, 1155, 1146, 1093, 1074, 1031, 951, 923, 912, 849, 802, 849, 802, 751, 732, 697 cm–1; HRMS (EI): calcd for (M)+ 465.1853, found 465.1850.
Acknowledgments
This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant No. JP18H04402 in Middle Molecular Strategy and JP17K05860, and AMED Grant No. JP19ak0101091h0002.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c01854.
Experimental details, spectral data, and copies of 1H, 13C{1H}, and 19F NMR spectra charts (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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