Abstract
Highly substituted isoquinolone-4-carboxylic acid is an important bioactive scaffold; however, it is challenging to access it in a general and short way. A Cu-catalyzed cascade reaction was successfully designed involving the Ugi postcyclization strategy by using ammonia and 2-halobenzoic acids as crucial building blocks. Privileged polysubstituted isoquinolin-1(2H)-ones were constructed in a combinatorial format with generally moderate to good yields. The protocol, with a ligand-free catalytic system, shows a broad substrate scope and good functional group tolerance toward excellent molecular diversity. Free 4-carboxy-isoquinolone is now for the first time generally accessible by a convergent multicomponent reaction protocol.
Introduction
Isoquinolin-1(2H)-one has attracted considerable attention as a privileged structure presented in numerous natural products of pharmaceutical interest such as ruprechstyril,1 pancratistatin,2 and gusanlung D3 (Figure 1A); it exhibits various biological activities, including antimicrobial,4 antifungal,5 analgesic,6 and antihypertensive7 activities. They also act as useful NK3 antagonists,8 5-HT3 receptor antagonists,9 chemoattractant receptor antagonist,10 and JNK inhibitors.11 In addition, the isoquinolin-1(2H)-one pharmacophore is employed to battle stomach tumors and human brain cell diseases.12 Interestingly, amide derivatives in the 4 position of this scaffold exhibit promising biological properties.5,6,13 As an intermediate in organic synthesis, substituted isoquinolin-1(2H)-ones are investigated on their further transformation to indenoisoquinolines, protoberberines, and dibenzoquinolizines as building blocks and key intermediates.14
Figure 1.
(A) Isoquinolin-1(2H)-one alkaloids; (B) Ugi-4CR/Heck sequence; (C) Ugi 4CR/Pd-catalyzed intramolecular arylation; (D) Ugi-4CR/Pd-catalyzed cascade reaction; (E) Ugi-4CR/Wittig sequence; and (F) Our work: Ammonia-Ugi 4-CR/Cu-catalyzed domino reaction.
Owning to the critical biological profiles, several procedures have been developed to obtain isoquinolin-1(2H)-one derivatives.15 However, the reported protocols suffer from a reduced precursor scope with only a few points of diversity and from a lengthy, sequential, overall low-yielding multistep synthesis.16 Based on the Ugi postcyclization strategy as a powerful tool to create structurally diverse heterocycles and large compound numbers in an atom and step economic, green manner,17 there are several reports on the synthesis of isoquinolone derivatives via the sequence of Ugi-MCR/post-condensation transformation.18 In 2004, the Yang group reported a synthesis of isoquinolones via the Ugi-4CR/Heck reaction (Figure 1B).18a Two years later, another Ugi-4CR and subsequent Pd-catalyzed intramolecular arylation reaction were published by them (Figure 1C).18b In 2012, the Chauhan group developed a ligand-free Pd-catalyzed cascade reaction to achieve diverse isoquinolone derivatives based on Ugi reaction (Figure 1D).16 Furthermore, Ding and co-workers provided a one-pot synthetic approach of isoquinolin-1(2H)-ones by a sequential Ugi-4CC/Wittig process (Figure 1E).18c However, none of them allow for the preparation of the target structure isoquinolone-4-carboxylic acid.
Based on prior intermolecular C–C coupling work19 and our experience in constructing diverse heterocyclic scaffolds via MCR chemistry,20 we envisaged that if Ugi reaction using the o-halobenzoic acids and ammonia as the starting materials and Cu-catalyzed C–C coupling/annulation reaction of the corresponding Ugi adducts and β-keto esters could be performed sequentially, it should lead to isoquinolin-1(2H)-ones alternatively (Figure 1F). We have previously shown a successful application of this strategy for the generation of tetraheterocyclic indenoisoquinolinones.20d It is the first report on the efficient synthesis of multisubstituted isoquinolone-4-carboxylic acid from readily accessible starting materials. Derivatization of the carboxyl group at this position is a hot spot in medicinal chemistry.5,6,13c
Results and Discussion
Ullmann-type condensations allow a variety of heterocycles to be constructed practically, representing efficient tools in the formation of C–heteroatom and C–C bonds.19,21 As the starting point of our work, the model Ugi reaction among o-iodobenzoic acid 1a, paraformaldehyde 3a, and tert-butyl isocyanide 4a in equimolar quantities and excessive ammonia water (25%) 2 was performed in trifluoroethanol under 60 °C for 12 h, affording the Ugi product 5a in 58% isolated yield. Thereafter, we investigated a copper-catalyzed tandem reaction involving acetoacetate to explore and optimize the Cu-catalyzed C–C coupling/annulation reaction conditions (Table 1). When the reaction of Ugi adduct 5a (0.3 mmol) with ethyl acetoacetate 6a (0.45 mmol) was carried out in dioxane (3.0 mL) at 80 °C for 12 h in a 10 mL round-bottom flask in the presence of CuSO4 (10 mol %) and Cs2CO3 (0.6 mmol), it led to the target product 7a1, albeit in low yield (32%, entry 1). Then, other copper catalysts were also evaluated (entries 2–4). Replacing the catalyst with CuCl2 or CuBr resulted in higher yields of 40 and 72%, respectively (entries 2–3). Gratifyingly, it was found that when CuI was employed, the yield of 7a1 increased to 82% (entry 4). As expected, without addition of a base, no product 7a1 can be detected (entry 5). Cs2CO3 was found to be better than K2CO3 (entry 4 vs entry 6) and was selected as the model base to further determine the scope and limitation of this methodology. The yield of 7a1 did not improve by increasing the amount of 6a to 2.0 equiv (entry 7). A variety of solvents were also examined. A diminished yield was obtained (42%) when CH3CN medium was employed (entry 8), while better yields were obtained when toluene and dimethylformamide were used (entries 9 and 10). For solvent selection, dioxane proved to be optimal in the outcome of this reaction (entry 4 vs entries 8–10). Moreover, only a trace amount of the product was detected without heating, even when the reaction time was extended to 18 h (entry 11). However, increasing the reaction temperature to 120 °C did not improve the yield (entry 12). Microwave irritation was also useful, but it produced isoquinolone-4-carboxylic acid 7a1 in a relatively lower yield (32%, entry 13). Thus, it can be concluded that the optimal conditions for the reaction of Ugi adduct 5a (1.0 equiv) and ethyl acetoacetate 6a (1.5 equiv) with Cs2CO3 (2.0 equiv) are as follows: in the presence of 10 mol % CuI, in dioxane (0.1 M), and at 80 °C for 12 h (entry 4).
Table 1. Optimization of Reaction Conditionsab.
| entry | 6 (equiv) | catalyst | base | solvent | T (°C) | yield 7a1c(%) |
|---|---|---|---|---|---|---|
| 1 | 1.5 | CuSO4 | Cs2CO3 | dioxane | 80 | 32 |
| 2 | 1.5 | CuCl2 | Cs2CO3 | dioxane | 80 | 40 |
| 3 | 1.5 | CuBr | Cs2CO3 | dioxane | 80 | 72 |
| 4 | 1.5 | CuI | Cs2CO3 | dioxane | 80 | 82 |
| 5 | 1.5 | CuI | dioxane | 80 | N.D.d | |
| 6 | 1.5 | CuI | K2CO3 | dioxane | 80 | 53 |
| 7 | 2.0 | CuI | Cs2CO3 | dioxane | 80 | 81 |
| 8 | 1.5 | CuI | Cs2CO3 | MeCN | 80 | 42 |
| 9 | 1.5 | CuI | Cs2CO3 | toluene | 80 | 60 |
| 10 | 1.5 | CuI | Cs2CO3 | DMF | 80 | 75 |
| 11e | 1.5 | CuI | Cs2CO3 | dioxane | r.t. | trace |
| 12 | 1.5 | CuI | Cs2CO3 | dioxane | 120 | 84 |
| 13f | 1.5 | CuI | Cs2CO3 | dioxane | 100 | 32 |
Reaction conditions: 5a (0.3 mmol), 6a, catalyst (10 mmol %), base (0.6 mmol), solvent (3 mL), 12 h.
TFE = 2,2,2-trifluoroethanol.
Isolated yields.
N.D. = not detected.
Reaction time is 18 h.
Under microwave irritation for 1 h.
Having established the optimized conditions, we synthesized several Ugi products to evaluate the substrate scope and limitations of the tandem reaction by reacting substituted 2-halogen benzoic acids with different aldehydes, isocyanides, and ammonia solution in TFE, followed by CuI-catalyzed cascade reaction, to give the corresponding isoquinolone-4-carboxylic acid derivatives 7a–t in fair to very good yields (Scheme 1). Paraformaldehyde was employed in several cases and underwent efficient domino reaction to give the desired products (7a-c, 7n, 7r-s) in moderate to good yields. With regard to the aliphatic aldehyde 3, we were pleased to see that a wide variety of substituents R2 (Scheme 1), including methyl (7d-e), isopropyl (7o), n-propyl (7f), 2-methylpropyl (7g), cyclopentyl (7h), 2-phenylethyl (7p), and 2-(methylthio)ethyl (7q), irrespective of the sterically hindered effect, could be installed to effectively deliver corresponding products. Subsequently, reactivity of aromatic aldehydes was examined. Aromatic aldehydes bearing an electron-donating para-methoxy group (7l) resulted in yields of isoquinolone derivatives that are similar to those obtained from aromatic aldehydes bearing an electron-withdrawing para-bromo group (7j). When benzaldehyde with a strong electron-withdrawing cyano substituent and unsubstituted benzaldehyde was employed, the yield of the desired compounds 7i and 7k decreased slightly to 63 and 66%, respectively. Also aldehyde possessing a heteroaromatic ring (7m) was an effective substrate for the reaction. For 2-halobenzoic acid substrates, electron-rich methoxy and methyl groups as well as nitro group were tolerated under the reaction conditions, and moderate to good yields were obtained (7n-s). It is noteworthy that when cyclopentanone (7t) was employed in the cascade reaction, only a trace amount of the desired product was observed by mass spectrometry (MS) analysis (Supporting Information), putatively due to steric hindrance.
Scheme 1. Copper-Catalyzed Domino Synthesis of Isoquinolone-4-Carboxylic Acid Derivatives.
The ammonia, aldehyde, carboxylic acid, isocyanide, and β-keto ester components are depicted with red, brown, blue, pink, and green, respectively.
The Ugi reaction was carried out using 1 (2.0 mmol), 2 (2.2 mmol), 3 (2.0 mmol), and 4 (2.0 mmol) in CF3CH2OH (1.0 M) for 12 h at 60 °C.
Reaction conditions: 5 (0.3 mmol), 6 (0.45 mmol), Cs2CO3 (0.6 mmol), CuI (0.03 mmol), dioxane (3 mL), 80 °C, 12 h.
Isolated yield.
N.D. = not detected.
Next, we investigated the reactivity of an array of Ugi adducts 5 derived from various isocyanides for the cascade reaction by reacting with ethyl acetoacetate 6a under the optimal conditions, as shown in Scheme 1. The reactions of Ugi adducts containing benzyl (7h, 7j, and 7n) and 2,3-dimethoxy benzyl groups (7g) with 6a gave the target products smoothly with 79, 78, 83, and 70% yields, respectively. Additionally, valuable functional groups such as 2,6-dimethyl-, 4-anisole-, and 2-ethyl-substituted isocyanobenzene can be expediently converted to isoquinolone-4-carboxylic acid derivatives (7c, 7e, and 7f, respectively). Moreover, (2-isocyanoethyl)benzene (7o) and 1-fluoro-4-(2-isocyanoethyl)benzene (7d) also furnished the different isoquinolone products in 74 and 62% yields, respectively. Furthermore, substrates bearing alkyl groups on the isocyanide component such as n-butyl (7b), cyclopropylmethyl (7k) tert-butyl (7a, 7l, 7m, 7p, 7q, and 7s), tert-octyl (7i), and 3-isopropoxypropyl (7r) could be well-accommodated. Lastly, the scope of β-keto esters was examined. The reactions also proceeded with the β-keto esters containing bigger isopropyl, propyl, and phenyl groups, but the yields of the corresponding products 7a2, 7a3, and 7a4 were lower, which illustrates that steric hindrance is a key factor. Of particular note is the fact that no reaction occurred when ethyl 4-chloroacetoacetate was subjected to the reaction conditions (7a5). The diversity of successful reactions shown in Scheme 1 clearly demonstrates that many functional groups in all four building blocks are compatible with the overall reaction sequence.
To further extend the scope of the product structures, we also performed this protocol with heteroaromatic 2-halo carboxylic acids. As shown in Scheme 2, product 5u derived from 2-chloro-3-quinolinecarboxylic acid reacted effectively with ethyl acetoacetate 6a under the present protocol, leading to the corresponding triheterocycle 7u in 52% yield. By contrast, the thiophene substrate 5v afforded the uncleaved 7v in good 77% yield.
Scheme 2. Heteroaromatic 2-Halocarboxylic Acids in the Ugi-4CR/Copper-Catalyzed Cascade Reaction.
Next, the ability to conduct the Ugi-4CR/copper-catalyzed cascade sequence reaction on a gram scale was accessed (Scheme 3, Supporting Information). A Ugi four-component reaction was conducted by reacting 2-iodobenzoic acid, ammonia, and cyclopentanecarbaldehyde with benzyl isocyanide on a 6 mmol scale. The Ugi product precipitated during the reaction and was filtered without further purification. It was reacted with ethyl acetoacetate, and we were pleased to observe the formation of 1.1 g of isoquinolone 7h (44% overall yield).
Scheme 3. Gram-Scale Reaction.
Lastly, we showed a synthetic application of the isoquinolone-4-carboxylic acids described herein. In situ acid chloride formation from 7a4 with oxalyl chloride and Friedel-Crafts cyclization provided indenoisoquinoline 8 in 58% yield (Scheme 4). This represents an efficient procedure to convert 7 into a medicinally relevant tetracyclic scaffold that has been reported as an inhibitor of topoisomerase I.22
Scheme 4. Transformation of 7a4.
Our hypothesized reaction mechanism for the cascade reaction is proposed as follows (Scheme 5). In the presence of a Cu(I) catalyst, ortho-directed Ullmann-type C–C coupling affords intermediate 9, which followed by the intramolecular condensation to form 10. The isoquinolone-4-carboxylic acids 7a-u could be generated through pathway A, and it involves the carbonate ion attacking the proton, which leads to the isoquinolin-1(2H)-one scaffold after the hydroxide ion leaves, followed by a final intramolecular SN2 reaction to the carboxylic acid product 7a-u, along with the formation of ethanol. In another case, the cascade reaction may also proceed through pathway B, through which 10 undergoes dehydration to give the product 7v.
Scheme 5. Proposed Reaction Mechanism.
Conclusions
In summary, we have developed an unprecedented, highly efficient approach to synthesize structurally very diverse isoquinolone-4-carboylic acids via a sequence of ammonia-Ugi-4CR/Cu-catalyzed domino reaction. The protocol has the advantages of being step economic, affording good yields, absence of ligands, and environmental friendliness, leading to its possible application in combinatorial and medicinal chemistry. Considering the operation easiness and the availability and simplicity of the starting materials of the protocol, we believe that this methodology will provide a promising method to access isoquinolin-1(2H)-one derivatives. Attempts to apply our recently developed automated nanosynthesis to this two-step sequence are ongoing and will be reported in due course.23
Experimental Section
General Information
Nuclear magnetic resonance spectra were recorded on a Bruker Avance 500 spectrometer. Chemical shifts for 1H NMR were reported relative to TMS (δ 0 ppm) or internal solvent peak (CDCl3 δ 7.26 ppm, CD3OD δ 3.31 ppm or D2O δ 4.79 ppm), and coupling constants were in hertz (Hz). The following abbreviations were used for spin multiplicity: s = singlet, d = doublet, t = triplet, dt = double triplet, ddd = doublet of double doublet, m = multiplet, and br = broad. Chemical shifts for 13C NMR are reported in ppm relative to the solvent peak (CDCl3 δ 77.23 ppm, DMSO δ 39.52 ppm, CD3OD δ 49.00 ppm). Filtrations were performed on a silica bed (Screening Devices BV, 60–200 μm, 60 Å). Flash chromatography was performed on a Grace Reveleris X2 using Grace Reveleris Silica columns (12 g), and a gradient of petroleum ether/ethyl acetate (0–100%) or dichloromethane/methanol (0–20%) was applied. Thin-layer chromatography was performed on Fluka precoated silica gel plates (0.20 mm thick, particle size 25 μm). Reagents were available from commercial suppliers and used without any purification, unless otherwise noted. All isocyanides were homemade by performing the Ugi,24 Hoffman,25 or Leukart–Wallach reductive amination procedure.26 Other reagents were purchased from Sigma Aldrich, ABCR, Acros, Fluorochem, and AK Scientific and were used without further purification. Mass spectra were measured on a Waters Investigator Supercritical Fluid Chromatograph with a 3100 MS Detector (ESI) using a solvent system of methanol and CO2 on a Viridis silica gel column (4.6 × 250 mm, 5 μm particle size) and reported as (m/z). High-resolution mass spectra (HRMS) were recorded using a LTQ-Orbitrap-XL (Thermo Fisher Scientific; ESI pos. mode) at a resolution of 60,000@m/z400. Melting points were obtained on a melting point apparatus and were uncorrected. Yields given refer to chromatographically purified compounds, unless otherwise stated. Compounds 5a, 5b, 5e, 5f, 5g, 5h, 5l, 5n, 5q, 5s, and 5u were all prepared following the reported literature protocols.20d
General Experimental Procedure and Characterization
Procedure A
A calculated volume of 25% ammonia solution (0.17 mL; 2.2 mmol; 1.1 equiv) was added to a stirred solution or suspension of the carboxylic acid (2 mmol; 1.0 equiv) in 2,2,2-trifluoroethanol (2 mL). The aldehyde (2 mmol; 1.0 equiv) and isocyanide (2 mmol; 1.0 equiv) were then introduced, and stirring was continued at 60 °C in a 4 mL screwed close vial in a heating metal block overnight. Solvent was removed by rotary evaporation, and the crude product was purified by column chromatography to give the desired product 5.
Procedure B
Ugi adduct 5 (0.3 mmol; 1.0 equiv), β–keto ester 6 (0.45 mmol; 1.5 equiv), Cs2CO3 (0.6 mmol; 2.0 equiv), and CuI (0.03 mmol; 0.1 equiv) were added to a 10 mL round-bottom flask equipped with a magnetic stir bar, and 3 mL of dioxane was added. The mixture was heated to 80 °C and reacted in an oil bath for 12 h. After the reaction was completed, solvent was removed by rotary evaporation, and the crude product was purified by column chromatography to give the desired product 7.
Gram-Scale Reaction Procedure of 7h
A 20 mL screwed close vial equipped with a magnetic stir bar was charged with a calculated volume of 25% ammonia solution (6.6 mmol; 1.1 equiv) and 2-iodobenzoic acid (0.51 mL; 6 mmol; 1.0 equiv) in 2,2,2-trifluoroethanol (6 mL). Then, cyclopentanecarbaldehyde (6 mmol; 1.0 equiv) and benzyl isocyanide (6 mmol; 1.0 equiv) were added to the solution, and the reaction was stirred at 60 °C in a sand bath overnight. The reaction mixture was washed with petroleum ether and filtered. The residue (1.78 g) was added to ethyl acetoacetate 6a (6 mmol) and Cs2CO3 (8 mmol) in dioxane (25 mL) and heated to 80 °C for 5 min, and then CuI (0.4 mol) was added and reacted in an oil bath for 12 h. The progress of the reaction was monitored by thin-layer chromatography. After the reaction was completed, solvent was removed by rotary evaporation and the crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 3:2) to afford the product 7h (1.1 g, 44% two-step yield).
Procedure C
Under an Ar atmosphere, 7a4 (56 mg, 0.15 mmol) was dissolved in CH2Cl2 (0.5 mL). At 0 °C, oxalyl chloride (32 ul, 0.3 mmol) and DMF (1 drop) were added, and the mixture was stirred for 2 h at rt. The reaction mixture was diluted with CH2Cl2 (0.5 mL), AlCl3 (49 mg, 0.36 mmol) was added, and it was further stirred for 1 h at rt. The mixture was diluted with sat. Rochelle salt (5 mL), the layers were separated, and the organic layer was dried over MgSO4, filtrated, and concentrated in vacuo. The remaining residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 3:2) to afford the product 8 as a red solid (31 mg, 58%).
N-(2-((2,6-Dimethylphenyl)amino)-2-oxoethyl)-2-iodobenzamide 5c
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5c (294 mg, 36%) as a yellow solid; mp: 176–177 °C; Rf = 0.39 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, Methanol-d4) δ 7.95 (dd, J = 7.9, 1.1 Hz, 1H), 7.54 (dd, J = 7.7, 1.8 Hz, 1H), 7.48 (td, J = 7.6, 1.1 Hz, 1H), 7.21 (td, J = 7.7, 1.8 Hz, 1H), 7.13 (d, J = 2.4 Hz, 3H), 4.26 (s, 2H), 2.29 (s, 6H). 13C{1H} NMR (126 MHz, Methanol-d4) δ 171.6, 168.7, 142.0, 139.6, 139.5, 135.7, 133.7, 130.9, 128.2, 127.7, 127.1, 91.8, 42.6, 17.2, 17.1. HRMS (ESI) m/z: [M + H]+ calcd for C17H18IN2O2, 409.0413; found, 409.0415.
N-(1-((4-Fluorophenethyl)amino)-1-oxopropan-2-yl)-2-iodobenzamide 5d
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5d (255 mg, 29%) as a yellow solid; mp: 165–166 °C; Rf = 0.42 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 7.83–7.77 (m, 1H), 7.42 (t, J = 5.8 Hz, 1H), 7.34–7.28 (m, 2H), 7.19 (d, J = 7.8 Hz, 1H), 7.12–7.04 (m, 3H), 6.91 (t, J = 8.7 Hz, 2H), 4.78 (p, J = 7.0 Hz, 1H), 3.53–3.42 (m, 1H), 3.41–3.33 (m, 1H), 2.75 (td, J = 7.2, 2.3 Hz, 2H), 1.43 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 172.1, 169.1, 161.5 (d, J = 244.2 Hz), 141.3, 139.9, 134.5 (d, J = 3.2 Hz), 131.3, 130.2 (d, J = 7.8 Hz), 128.2 (d, J = 14.4 Hz), 115.3, 115.2, 92.6, 49.4, 40.9, 34.7, 18.8. HRMS (ESI) m/z: [M + H]+ calcd for C18H19FIN2O2, 441.0475; found, 441.0487.
N-(1-(4-Cyanophenyl)-2-oxo-2-((2,4,4-trimethylpentan-2-yl)amino)ethyl)-2-iodobenzamide 5i
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5i (259 mg, 25%) as a yellow solid; mp: 162–163 °C; Rf = 0.48 (30% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 7.92–7.85 (m, 1H), 7.71–7.62 (m, 4H), 7.58 (d, J = 7.0 Hz, 1H), 7.40 (dd, J = 7.0, 1.6 Hz, 2H), 7.15 (ddd, J = 8.0, 6.6, 2.6 Hz, 1H), 6.52 (s, 1H), 5.91 (d, J = 7.0 Hz, 1H), 1.69–1.54 (m, 2H), 1.27 (d, J = 17.2 Hz, 6H), 0.80 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 169.0, 166.9, 143.2, 140.9, 140.1, 132.6, 131.6, 128.3, 128.2, 118.5, 112.1, 92.4, 57.5, 56.1, 51.5, 31.4, 31.2, 29.0, 28.5. HRMS (ESI) m/z: [M + H]+ calcd for C24H29IN3O2, 518.1304; found, 518.1307.
N-(2-(Benzylamino)-1-(4-bromophenyl)-2-oxoethyl)-2-iodobenzamide 5j
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5j (547 mg, 50%) as a yellow solid; mp: 172–173 °C; Rf = 0.49 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.13 (dd, J = 8.2, 3.1 Hz, 1H), 8.84 (q, J = 5.8 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.61–7.56 (m, 2H), 7.51 (dd, J = 8.9, 3.0 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.39–7.34 (m, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.27–7.15 (m, 4H), 5.72 (dd, J = 8.4, 4.4 Hz, 1H), 4.33 (qd, J = 15.3, 5.7 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 169.6, 169.0, 142.6, 139.4, 138.2, 131.7, 131.5, 131.4, 130.3, 130.2 (d, J = 21.5 Hz), 128.9, 128.8, 128.3, 127.6, 127.3, 121.4, 94.0, 56.7, 42.7. HRMS (ESI) m/z: [M + H]+ calcd for C22H19BrIN2O2, 548.9675; found, 548.9676.
N-(2-((Cyclopropylmethyl)amino)-2-oxo-1-phenylethyl)-2-iodobenzamide 5k
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5k (304 mg, 35%) as a yellow solid; mp: 183–184 °C; Rf = 0.78 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 7.88 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 6.9, 1.8 Hz, 2H), 7.43 (dd, J = 7.6, 1.8 Hz, 2H), 7.40–7.32 (m, 4H), 7.12 (td, J = 7.7, 1.8 Hz, 1H), 6.61 (t, J = 5.5 Hz, 1H), 5.87 (d, J = 7.2 Hz, 1H), 3.34–2.69 (m, 2H), 0.86 (tt, J = 7.5, 4.8 Hz, 1H), 0.39 (dd, J = 8.2, 1.5 Hz, 2H), 0.19–0.10 (m, 2H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 169.5, 168.7, 141.2, 140.0, 137.8, 131.4, 128.9, 128.5, 128.4, 128.1, 127.5, 92.5, 57.5, 44.7, 10.4, 3.4 (d, J = 3.6 Hz). HRMS (ESI) m/z: [M + H]+ calcd for C19H20IN2O2, 435.0569; found, 435.0576.
N-(2-(Tert-butylamino)-2-oxo-1-(pyridin-2-yl)ethyl)-2-iodobenzamide 5m
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5m (245 mg, 28%) as a white solid; mp: 193–194 °C; Rf = 0.26 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.57 (dt, J = 4.7, 1.5 Hz, 1H), 7.94 (dt, J = 7.9, 1.7 Hz, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.74 (tt, J = 7.8, 1.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.54 (dd, J = 7.7, 1.7 Hz, 1H), 7.43 (ddt, J = 7.5, 6.2, 1.6 Hz, 1H), 7.28–7.24 (m, 1H), 7.16 (td, J = 7.6, 1.7 Hz, 1H), 7.11 (s, 1H), 5.63 (d, J = 5.6 Hz, 1H), 1.34 (d, J = 1.8 Hz, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 169.0, 167.0, 155.8, 148.8, 141.2, 140.2, 137.2, 131.5, 128.6, 128.2, 123.0, 121.2, 92.6, 58.8, 51.8, 28.7. HRMS (ESI) m/z: [M + H]+ calcd for C18H21IN3O2, 438.0678; found, 438.0680.
2-Bromo-4-methoxy-N-(3-methyl-1-oxo-1-(phenethylamino)butan-2-yl)benzamide 5o
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5o (311 mg, 36%) as a brown solid; mp: 164–165 °C; Rf = 0.46 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 7.53 (d, J = 8.6 Hz, 1H), 7.34–7.28 (m, 2H), 7.26–7.18 (m, 3H), 7.13 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.6, 2.5 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 4.49–4.38 (m, 1H), 3.84 (s, 3H), 3.62 (dt, J = 13.4, 6.7 Hz, 1H), 3.54 (dt, J = 13.4, 6.6 Hz, 1H), 2.85 (t, J = 7.1 Hz, 2H), 2.21 (q, J = 6.7 Hz, 1H), 1.00 (dd, J = 6.8, 1.8 Hz, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 170.7, 167.1, 161.3, 138.7, 131.3, 129.1, 128.8, 128.7, 126.6, 120.2, 118.8, 113.4, 59.3, 55.7, 40.7, 35.7, 31.2, 19.4, 18.3. HRMS (ESI) m/z: [M + H]+ calcd for C21H26BrN2O3, 433.1127; found, 433.1129.
N-(1-(Tert-butylamino)-1-oxo-4-phenylbutan-2-yl)-2-iodo-4-methoxybenzamide 5p
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5p (393 mg, 44%) as a yellow solid; mp: 160–161 °C; Rf = 0.45 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 7.49 (d, J = 8.6 Hz, 1H), 7.35–7.26 (m, 2H), 7.25–7.19 (m, 3H), 7.13 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.6, 2.5 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.17 (s, 1H), 4.59 (td, J = 7.5, 6.0 Hz, 1H), 3.84 (s, 3H), 2.78 (ddd, J = 13.3, 9.6, 6.2 Hz, 2H), 2.27 (ddt, J = 13.9, 9.8, 6.3 Hz, 1H), 2.09 (dddd, J = 13.6, 9.7, 7.3, 6.1 Hz, 1H), 1.39 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 170.1, 167.0, 161.3, 141.0, 131.0, 129.2, 128.5, 128.4, 126.1, 120.3, 118.7, 113.4, 55.7, 53.9, 51.6, 34.2, 31.8, 28.7. HRMS (ESI) m/z: [M + H]+ calcd for C22H28IN2O3, 447.1283; found, 447.1288.
2-Bromo-N-(2-((3-isopropoxypropyl)amino)-2-oxoethyl)-4-methylbenzamide 5r
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5r (333 mg, 45%) as a yellow solid; mp: 199–200 °C; Rf = 0.36 (100% EtOAc). 1H NMR (500 MHz, Chloroform-d) δ 7.44 (dd, J = 7.7, 4.0 Hz, 1H), 7.41 (t, J = 1.6 Hz, 1H), 7.19–7.12 (m, 1H), 7.11–7.07 (m, 1H), 6.93 (t, J = 5.5 Hz, 1H), 4.11 (dd, J = 5.0, 2.3 Hz, 2H), 3.58–3.51 (m, 1H), 3.51–3.46 (m, 2H), 3.39 (q, J = 6.2 Hz, 2H), 2.35 (d, J = 2.6 Hz, 3H), 1.77 (ddt, J = 12.4, 8.1, 4.4 Hz, 2H), 1.16–1.10 (m, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 168.1, 167.8, 142.2, 133.9, 133.1, 129.6, 128.3, 119.3, 71.8, 66.7, 43.6, 38.3, 29.3, 22.1, 21.0. HRMS (ESI) m/z: [M + H]+ calcd for C16H24BrN2O3, 371.0970; found, 371.0989.
N-(1-(Benzylcarbamoyl)cyclopentyl)-2-iodobenzamide 5t
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5t (367 mg, 41%) as a yellow solid; mp: 175–176 °C; Rf = 0.52 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J = 2.9 Hz, 1H), 8.05 (q, J = 5.2 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 4.5 Hz, 4H), 7.22 (q, J = 4.2 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 4.36 (d, J = 6.0 Hz, 2H), 2.13 (t, J = 6.4 Hz, 4H), 1.83–1.73 (m, 2H), 1.68 (t, J = 5.7 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 173.7, 169.4, 143.2, 140.5, 139.3, 139.1, 131.1, 129.2, 128.6, 127.3, 126.9, 93.9, 67.4, 42.9, 36.5, 24.6. HRMS (ESI) m/z: [M + H]+ calcd for C20H22IN2O2, 449.0726; found, 449.0733.
N-(2-(Benzylamino)-2-oxoethyl)-2-bromothiophene-3-carboxamide 5v
It was synthesized according to procedure A on a 2 mmol scale, which afforded 5v (253 mg, 36%) as a white solid; mp: 165–166 °C; Rf = 0.25 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 7.58 (t, J = 4.9 Hz, 1H), 7.33 (dt, J = 6.9, 1.4 Hz, 1H), 7.32–7.27 (m, 5H), 7.23–7.18 (m, 2H), 4.49 (d, J = 5.7 Hz, 2H), 4.23 (d, J = 5.0 Hz, 2H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 168.5, 162.4, 137.8, 134.7, 129.0, 128.7, 127.8, 127.6, 126.3, 113.9, 43.7. HRMS (ESI) m/z: [M + H]+ calcd for C14H14BrN2O2S, 352.9959; found, 352.9957.
2-(2-(Tert-butylamino)-2-oxoethyl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7a1
It was synthesized according to procedure B on 0.3 mmol scale, which afforded 7a1 (78 mg, 82%) as a white solid; mp: 257–258 °C; Rf = 0.41 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.35 (dd, J = 7.6, 1.4 Hz, 1H), 7.72–7.58 (m, 2H), 7.37 (ddd, J = 8.0, 5.8, 2.4 Hz, 1H), 5.57 (s, 1H), 4.70 (s, 2H), 2.66 (s, 3H), 1.39 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.0, 170.0, 165.7, 163.1, 134.0, 133.3, 129.6, 125.4, 124.2, 122.5, 100.1, 51.8, 43.4, 28.8, 25.2. HRMS (ESI) m/z: [M + H]+ calcd for C17H21N2O4, 317.1501; found, 317.1502.
2-(2-(Butylamino)-2-Oxoethyl)-3-Methyl-1-Oxo-1,2-Dihydroisoquinoline-4-Carboxylic Acid 7b
It was synthesized according to procedure B on 0.3 mmol scale, which afforded 7b (71 mg, 75%) as a white solid; mp: 248–249 °C; Rf = 0.35 (40% EtOAc/dichloromethane). 1H NMR (500 MHz, DMSO-d6) δ 9.18 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.75 (t, J = 5.7 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H), 4.54 (s, 2H), 3.04 (q, J = 6.6 Hz, 2H), 2.39 (s, 3H), 1.37 (q, J = 7.2 Hz, 2H), 1.29 (p, J = 7.2 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 194.1, 169.0, 164.4, 140.9, 131.9, 127.4, 127.2, 123.3, 119.2 (d, J = 12.7 Hz), 117.9, 96.9, 42.6, 38.7, 34.3, 31.8, 20.0, 14.2. HRMS (ESI) m/z: [M + H]+ calcd for C17H21N2O4, 317.1501; found, 317.1502.
2-(2-((2,6-Dimethylphenyl)amino)-2-oxoethyl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7c
It was synthesized according to procedure B on 0.3 mmol scale, which afforded 7c (87 mg, 80%) as a yellow solid; mp: 260–261 °C; Rf = 0.32 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 9.21 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.04 (s, 3H), 6.85 (t, J = 7.3 Hz, 1H), 4.81 (s, 2H), 2.44 (s, 3H), 2.19 (s, 6H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 194.1, 168.1, 164.5, 140.9, 135.9, 135.8, 131.9, 127.9, 127.4, 127.3, 126.6, 123.4, 119.2, 117.9, 96.9, 42.7, 18.7, 18.6. HRMS (ESI) m/z: [M + H]+ calcd for C21H21N2O4, 365.1501; found, 365.1505.
2-(1-((4-Fluorophenethyl)amino)-1-oxopropan-2-yl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7d
It was synthesized according to procedure B on 0.3 mmol scale, which afforded 7d (74 mg, 62%) as a yellow solid; mp: 274–275 °C; Rf = 0.38 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.91 (s, 1H), 7.21 (s, 4H), 7.01 (s, 2H), 6.84 (s, 1H), 5.53 (s, 1H), 3.26 (s, 1H), 3.12 (s, 1H), 2.64 (s, 2H), 2.40 (s, 3H), 1.56–0.90 (m, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 194.3, 171.7, 164.1, 161.1 (d, J = 241.1 Hz), 140.9, 136.6, 131.9, 130.9 (d, J = 7.8 Hz), 127.4 (d, J = 20.6 Hz), 123.2, 119.2, 118.2, 115.3 (d, J = 20.6 Hz), 97.3, 48.7, 41.1, 34.9, 34.4, 15.0. HRMS (ESI) m/z: [M + H]+ calcd for C22H22FN2O4, 397.1564; found, 397.1549.
3-Methyl-1-oxo-2-(1-oxo-1-((4-phenoxyphenyl)amino)propan-2-yl)-1,2-dihydroisoquinoline-4-carboxylic Acid 7e
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7e (101 mg, 76%) as a yellow solid; mp: 268–269 °C; Rf = 0.34 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, Acetone-d6) δ 9.31 (d, J = 8.6 Hz, 1H), 9.20 (s, 1H), 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.68 (dd, J = 8.8, 2.3 Hz, 2H), 7.35 (dd, J = 8.6, 7.3 Hz, 2H), 7.29 (ddd, J = 8.6, 6.6, 1.5 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 7.00–6.93 (m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.84 (t, J = 7.3 Hz, 1H), 5.89 (q, J = 6.7 Hz, 1H), 2.48 (s, 3H), 1.54 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (126 MHz, Acetone-d6) δ 194.5, 171.3, 164.4, 164.1, 158.1, 152.1, 141.2, 135.9, 131.4, 129.7, 127.3 (d, J = 10.4 Hz), 123.4, 122.7, 121.5 (d, J = 21.2 Hz), 119.2, 118.7, 118.2, 117.9, 97.4, 49.7, 33.5, 14.0. HRMS (ESI) m/z: [M + H]+ calcd for C26H23N2O5, 443.1607; found, 443.1612.
2-(1-((2-Ethylphenyl)amino)-1-oxopentan-2-yl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7f
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7f (83 mg, 68%) as a yellow solid; mp: 271–272 °C; Rf = 0.49 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.36 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.65 (dq, J = 19.0, 10.9, 9.4 Hz, 3H), 7.40 (t, J = 7.4 Hz, 1H), 7.24–7.15 (m, 3H), 7.11 (t, J = 7.5 Hz, 1H), 5.83 (dd, J = 9.2, 6.0 Hz, 1H), 2.66 (s, 3H), 2.56 (q, J = 7.6 Hz, 2H), 2.45–2.22 (m, 2H), 1.43–1.31 (m, 2H), 1.16 (t, J = 7.5 Hz, 3H), 0.98 (t, J = 7.3 Hz, 4H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.5, 170.1, 167.8, 163.7, 135.0, 134.9, 133.9, 133.5, 129.7, 128.6, 126.7, 125.7, 125.4, 124.2, 123.5, 122.6, 100.0, 55.9, 30.4, 25.2, 24.4, 19.8, 14.0, 13.8. HRMS (ESI) m/z: [M + H]+ calcd for C24H27N2O4, 407.1971; found, 407.1969.
2-(1-((2,3-Dimethoxybenzyl)amino)-4-methyl-1-oxopentan-2-yl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7g
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7 g (98 mg, 70%) as a yellow solid; mp: 242–243 °C; Rf = 0.34 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.32 (dd, J = 7.9, 1.5 Hz, 1H), 7.73–7.57 (m, 2H), 7.37 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.91 (dd, J = 7.7, 1.4 Hz, 1H), 6.86 (dd, J = 8.0, 1.5 Hz, 1H), 6.25 (t, J = 5.7 Hz, 1H), 5.72 (dd, J = 9.8, 5.0 Hz, 1H), 4.65–4.38 (m, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 2.64 (s, 3H), 2.24 (ddd, J = 14.2, 9.8, 4.6 Hz, 1H), 2.01 (ddd, J = 14.0, 9.2, 5.1 Hz, 1H), 1.44 (q, J = 4.8 Hz, 1H), 0.96 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.1, 170.1, 169.5, 163.3, 152.5, 147.1, 133.9, 133.3, 131.7, 129.7, 125.5, 124.2, 124.2, 122.7, 121.4, 111.8, 100.1, 60.7, 55.7, 53.5, 39.2, 37.4, 25.5, 25.2, 23.3, 22.1. HRMS (ESI) m/z: [M + H]+ calcd for C26H31N2O6, 467.2182; found, 467.2185.
2-(2-(Benzylamino)-1-cyclopentyl-2-oxoethyl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7h
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7 h (99 mg, 79%) as red oil; Rf = 0.36 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.31 (dd, J = 8.0, 1.7 Hz, 1H), 7.76–7.57 (m, 2H), 7.41–7.35 (m, 1H), 7.34–7.30 (m, 2H), 7.30–7.23 (m, 3H), 6.31 (s, 1H), 5.46 (d, J = 10.5 Hz, 1H), 4.58 (dd, J = 14.9, 6.1 Hz, 1H), 4.42 (dd, J = 15.0, 5.3 Hz, 1H), 3.26–3.03 (m, 1H), 2.65 (s, 3H), 2.18 (dq, J = 13.8, 7.3 Hz, 1H), 1.72 (ddd, J = 7.9, 5.3, 2.8 Hz, 2H), 1.61 (dq, J = 12.3, 4.3, 3.0 Hz, 1H), 1.54–1.41 (m, 3H), 1.22–1.03 (m, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.3, 170.1, 169.4, 163.7, 138.3, 133.9, 133.4, 129.7, 128.6, 127.6, 127.4, 125.5, 124.2, 122.6, 99.9, 60.3, 43.6, 38.3, 32.1, 30.2, 25.7, 25.2, 24.7. HRMS (ESI) m/z: [M + H]+ calcd for C25H27N2O4, 419.1971; found, 419.1974.
2-(1-(4-Cyanophenyl)-2-oxo-2-((2,4,4-trimethylpentan-2-yl)amino)ethyl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7i
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7i (89 mg, 63%) as a yellow solid; mp: 263–264 °C; Rf = 0.44 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.32 (dd, J = 8.0, 1.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.72–7.66 (m, 2H), 7.65 (ddd, J = 8.5, 6.9, 1.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.42–7.34 (m, 1H), 6.58 (s, 1H), 5.44 (s, 1H), 2.64 (s, 3H), 1.69 (d, J = 15.0 Hz, 1H), 1.56 (d, J = 15.0 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 0.90 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.1, 169.9, 165.0, 163.2, 140.4, 133.8, 133.6, 132.6, 131.0, 129.7, 125.7, 124.3, 122.7, 118.3, 112.7, 100.4, 59.6, 56.2, 53.0, 31.5, 31.4, 28.4 (d, J = 9.1 Hz), 25.1. HRMS (ESI) m/z: [M + H]+ calcd for C28H32N3O4, 474.2393; found, 474.2397.
2-(2-(Benzylamino)-1-(4-bromophenyl)-2-oxoethyl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7j
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7j (118 mg, 78%) as a yellow solid; mp: 255–256 °C; Rf = 0.46 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.42–8.25 (m, 1H), 7.73–7.56 (m, 4H), 7.51 (d, J = 8.2 Hz, 2H), 7.42–7.24 (m, 6H), 6.65 (s, 1H), 6.01 (q, J = 5.4, 4.9 Hz, 1H), 4.59 (dd, J = 15.1, 6.0 Hz, 1H), 4.49 (dd, J = 15.1, 5.6 Hz, 1H), 2.64 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 182.9, 169.9, 167.1, 163.2, 138.0, 133.9, 133.8, 133.5, 132.3, 132.2, 129.7, 128.7, 127.7, 127.5, 125.6, 124.2, 123.4, 122.8, 100.5, 58.7, 44.0, 25.1. HRMS (ESI) m/z: [M + H]+ calcd for C26H22BrN2O4, 505.0763; found, 505.0763.
2-(2-((Cyclopropylmethyl)amino)-2-oxo-1-phenylethyl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7k
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7k (77 mg, 66%) as a white solid; mp: 241–242 °C; Rf = 0.26 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.14 (dd, J = 8.7, 1.2 Hz, 1H), 7.90 (dd, J = 8.0, 1.7 Hz, 1H), 7.41–7.37 (m, 2H), 7.32–7.24 (m, 4H), 7.22–7.16 (m, 1H), 6.84 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.67 (s, 1H), 3.07–2.86 (m, 2H), 2.39 (s, 3H), 0.99–0.78 (m, 1H), 0.33 (dtd, J = 8.2, 3.4, 2.0 Hz, 2H), 0.14 (dd, J = 4.9, 3.0 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 194.5, 169.6, 164.4, 164.3, 140.9, 138.5, 132.2, 129.8, 128.0, 127.6 (d, J = 23.3 Hz), 127.1, 123.2, 119.4 (d, J = 15.5 Hz), 118.0, 97.2, 79.8 (d, J = 11.0 Hz), 57.4 (d, J = 17.4 Hz), 43.5, 34.3 (d, J = 5.0 Hz), 11.4 (d, J = 9.2 Hz), 3.55. HRMS (ESI) m/z: [M + H]+ calcd for C23H23N2O4, 391.1658; found, 391.1660.
2-(2-(Tert-butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7l
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7l (95 mg, 75%) as a yellow solid; mp: 268–270 °C; Rf = 0.35 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.33 (dd, J = 7.9, 1.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.63–7.56 (m, 2H), 7.35 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.52 (s, 1H), 5.56 (s, 1H), 3.83 (s, 3H), 2.62 (s, 3H), 1.36 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 182.4, 170.1, 166.9, 163.2, 159.9, 133.9, 133.1, 131.9, 129.7, 127.4, 125.4, 124.1, 123.1, 114.4, 100.5, 59.4, 55.3, 51.7, 28.6, 25.0. HRMS (ESI) m/z: [M + H]+ calcd for C24H27N2O5, 423.1920; found, 423.1920.
2-(2-(Tert-butylamino)-2-oxo-1-(pyridin-2-yl)ethyl)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7m
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7m (76 mg, 64%) as a yellow solid; mp: 248–249 °C; Rf = 0.22 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 9.71 (s, 1H), 8.61 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 8.37 (dt, J = 7.9, 1.1 Hz, 1H), 7.76–7.55 (m, 3H), 7.39 (ddd, J = 8.1, 5.4, 2.9 Hz, 1H), 7.27–7.24 (m, 1H), 7.10 (dd, J = 8.1, 1.0 Hz, 1H), 6.75 (s, 1H), 2.67 (s, 3H), 1.45 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 182.9, 170.2, 164.6, 163.3, 156.0, 147.6, 137.5, 134.1, 133.4, 129.9, 125.5, 124.2, 122.8, 122.2, 120.9, 100.4, 57.3, 51.3, 28.7, 25.2. HRMS (ESI) m/z: [M + H]+ calcd for C22H24N3O4, 394.1767; found, 394.1763.
2-(2-(Benzylamino)-2-oxoethyl)-7-methoxy-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7n
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7n (95 mg, 83%) as a yellow solid; mp: 250–251 °C; Rf = 0.42 (80% EtOAc/petroleum ether). 1H NMR (500 MHz, DMSO-d6) δ 9.23 (d, J = 9.3 Hz, 1H), 8.29 (s, 1H), 7.42 (d, J = 3.1 Hz, 1H), 7.31 (d, J = 6.2 Hz, 4H), 7.23 (td, J = 6.0, 2.7 Hz, 1H), 6.97 (dd, J = 9.3, 3.1 Hz, 1H), 4.64 (s, 2H), 4.28 (d, J = 6.0 Hz, 2H), 3.74 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 193.4, 169.5, 164.1, 164.0, 152.9, 140.2, 135.3, 128.6, 127.6, 127.0, 125.5, 121.3, 118.5, 108.2, 96.4, 42.9, 42.4, 40.7, 34.3. HRMS (ESI) m/z: [M + H]+ calcd for C21H21N2O5, 381.1450; found, 381.1454.
6-Methoxy-3-methyl-2-(3-methyl-1-oxo-1-(phenethylamino)butan-2-yl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7o
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7o (97 mg, 74%) as a brown solid; mp: 275–276 °C; Rf = 0.36 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.26 (d, J = 8.8 Hz, 1H), 7.11 (tdd, J = 9.5, 6.3, 3.5 Hz, 5H), 7.06 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 8.8, 2.4 Hz, 1H), 6.23 (s, 1H), 5.15 (d, J = 10.3 Hz, 1H), 3.95 (s, 3H), 3.64 (dq, J = 13.2, 6.6 Hz, 1H), 3.49–3.37 (m, 1H), 2.93 (dp, J = 10.3, 6.6 Hz, 1H), 2.88–2.73 (m, 2H), 2.67 (s, 3H), 1.15 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.7, 170.4, 169.0, 163.7, 163.4, 138.9, 135.8, 132.1, 128.7, 128.4, 126.2, 115.9, 111.6, 109.3, 99.8, 55.6, 40.6, 35.5, 26.4, 25.4, 21.5, 19.1. HRMS (ESI) m/z: [M + H]+ calcd for C25H29N2O5, 437.2076; found, 437.2085.
2-(1-(Tert-butylamino)-1-oxo-4-phenylbutan-2-yl)-6-methoxy-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7p
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7p (88 mg, 65%) as a yellow solid; mp: 244–245 °C; Rf = 0.34 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.28 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 7.5 Hz, 2H), 7.14–7.06 (m, 3H), 7.02 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 8.9, 2.3 Hz, 1H), 5.66–5.57 (m, 1H), 5.46 (s, 1H), 3.93 (s, 3H), 2.79–2.69 (m, 1H), 2.63 (s, 3H), 2.62–2.57 (m, 1H), 2.56–2.47 (m, 2H), 1.33 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 183.3, 170.3, 168.4, 163.5, 163.0, 140.9, 135.8, 132.0, 128.3 (d, J = 2.3 Hz), 125.9, 116.0, 111.5, 109.4, 100.1, 55.6, 55.3, 51.5, 32.8, 29.6, 28.7, 25.3. HRMS (ESI) m/z: [M + H]+ calcd for C26H31N2O5, 451.2233; found, 451.2238.
2-(1-(Tert-butylamino)-4-(methylthio)-1-oxobutan-2-yl)-3,7-dimethyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7q
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7q (73 mg, 60%) as a yellow solid; mp: 269–270 °C; Rf = 0.39 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.14 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 5.66 (dd, J = 8.8, 5.2 Hz, 1H), 5.45 (s, 1H), 2.64 (s, 3H), 2.60–2.55 (m, 1H), 2.55–2.50 (m, 1H), 2.46–2.43 (m, 3H), 2.44–2.41 (m, 1H), 2.39–2.37 (dt, J = 8.7, 4.4 Hz, 1H), 2.08 (s, 3H), 1.33 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 182.6, 170.0, 168.0, 163.5, 135.6, 134.6, 131.2, 129.6, 124.2, 122.5, 100.0, 54.5, 51.6, 31.3, 28.7, 28.0, 25.1, 20.8, 15.5. HRMS (ESI) m/z: [M + H]+ calcd for C21H29N2O4S, 405.1848; found, 405.1850.
2-(2-((3-Isopropoxypropyl)amino)-2-oxoethyl)-3,6-dimethyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7r
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7r (88 mg, 78%) as a white solid; mp: 239–240 °C; Rf = 0.55 (10% MeOH/ dichloromethane). 1H NMR (500 MHz, Acetone-d6) δ 9.17 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 6.69 (dd, J = 8.1, 1.7 Hz, 1H), 4.69 (s, 2H), 3.48 (p, J = 6.1 Hz, 1H), 3.40 (t, J = 6.1 Hz, 2H), 3.25 (q, J = 6.2 Hz, 2H), 2.51 (s, 3H), 2.31 (s, 3H), 1.67 (t, J = 6.4 Hz, 2H), 1.05 (d, J = 6.0 Hz, 6H). 13C{1H} NMR (126 MHz, Acetone-d6) δ 194.6, 170.2, 164.6, 141.1 (d, J = 2.1 Hz), 127.3, 127.2, 123.3, 120.4, 120.3, 115.8, 97.0, 71.0 (d, J = 6.9 Hz), 65.4, 43.5, 36.5, 36.3, 33.5, 29.9, 21.6. HRMS (ESI) m/z: [M + H]+ calcd for C20H27N2O5, 375.1920; found, 375.1908.
2-(2-(Tert-butylamino)-2-oxoethyl)-3-methyl-6-nitro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7s
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7s (93 mg, 86%) as a yellow solid; mp: 271–272 °C; Rf = 0.25 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, Methanol-d4) δ 10.12 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.73 (dd, J = 8.7, 2.4 Hz, 1H), 4.75 (s, 2H), 2.62 (s, 3H), 1.39 (s, 9H). 13C{1H} NMR (126 MHz, Methanol-d4) δ 197.7, 168.7, 165.1, 164.3, 160.0, 150.8, 140.4, 128.4, 121.3, 113.2, 98.1, 50.7, 42.9, 31.9, 27.7. HRMS (ESI) m/z: [M + H]+ calcd for C17H20N3O6, 362.1352; found, 362.1354.
2-(2-(Tert-butylamino)-2-oxoethyl)-3-isopropyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic Acid 7a2
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7a2 (54 mg, 52%) as a yellow solid; mp: 245–246 °C; Rf = 0.52 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Methanol-d4) δ 8.59 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 4.78 (s, 2H), 4.13 (s, 1H), 1.38 (s, 9H), 1.17 (d, J = 6.5 Hz, 6H). 13C{1H} NMR (126 MHz, Methanol-d4) δ 207.6, 169.1, 165.4, 163.4, 140.2, 132.2, 127.0, 122.9, 120.0, 117.6, 97.8, 50.6, 43.1, 27.8 (d, J = 15.1 Hz), 19.5, 19.0. HRMS (ESI) m/z: [M + H]+ calcd for C19H25N2O4, 345.1814; found, 345.1811.
2-(2-(Tert-butylamino)-2-oxoethyl)-1-oxo-3-propyl-1,2-dihydroisoquinoline-4-carboxylic Acid 7a3
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7a3 (60 mg, 58%) as a white solid; mp: 231–232 °C; Rf = 0.55 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.34 (dd, J = 7.9, 1.5 Hz, 1H), 7.64 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.37 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 5.60 (s, 1H), 4.70 (s, 2H), 2.93–2.84 (m, 2H), 1.98–1.85 (m, 2H), 1.38 (s, 9H), 1.11 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 186.4, 170.1, 165.7, 163.1, 133.9, 133.3, 129.5, 125.4, 124.2, 122.6, 99.7, 51.8, 43.5, 38.6, 28.8, 19.6, 14.1. HRMS (ESI) m/z: [M + H]+ calcd for C19H25N2O4, 345.1814; found, 345.1816.
2-(2-(Tert-butylamino)-2-oxoethyl)-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-carboxylic Acid 7a4
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7a4 (45 mg, 40%) as a yellow solid; mp: 261–262 °C; Rf = 0.42 (40% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.24 (dd, J = 7.9, 1.6 Hz, 1H), 7.57 (dtd, J = 7.0, 4.0, 3.4, 1.4 Hz, 3H), 7.51–7.45 (m, 2H), 7.23 (ddd, J = 8.0, 7.2, 1.1 Hz, 1H), 7.16 (ddd, J = 8.6, 7.2, 1.6 Hz, 1H), 6.85 (dd, J = 8.3, 1.1 Hz, 1H), 5.61 (s, 1H), 4.75 (s, 2H), 1.41 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 180.4, 170.4, 165.7, 163.2, 136.0, 133.5, 132.1, 131.5, 129.1, 128.9, 128.7, 125.7, 125.6, 122.7, 99.2, 51.9, 43.5, 28.9. HRMS (ESI) m/z: [M + H]+ calcd for C22H23N2O4, 379.1658; found, 379.1660.
2-(2-(Tert-butylamino)-2-oxoethyl)-3-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic Acid 7u
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7u (57 mg, 52%) as a yellow solid; mp: 248–249 °C; Rf = 0.49 (50% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 9.13 (s, 1H), 7.97–7.93 (m, 1H), 7.88 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.56 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 5.58 (s, 1H), 4.71 (s, 2H), 2.79 (s, 3H), 1.40 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 200.9, 166.3, 163.6, 161.1, 150.0, 143.5, 138.1, 135.2, 130.2, 126.0, 122.5, 118.7, 117.3, 95.6, 51.7, 43.4, 32.1, 28.9. HRMS (ESI) m/z: [M + H]+ calcd for C20H22N3O4, 368.1610; found, 368.1612.
Ethyl 5-(2-(benzylamino)-2-oxoethyl)-6-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxylate 7v
It was synthesized according to procedure B on a 0.3 mmol scale, which afforded 7v (89 mg, 77%) as a yellow solid; mp: 267–268 °C; Rf = 0.38 (70% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 7.53 (d, J = 5.5 Hz, 1H), 7.32 (d, J = 5.5 Hz, 1H), 7.28–7.19 (m, 6H), 4.91 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 4.41 (d, J = 5.8 Hz, 2H), 2.89 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 167.2, 165.5, 159.5, 148.0, 147.3, 137.8, 128.6, 127.7, 127.5, 127.4, 126.8, 124.3, 107.7, 61.8, 48.3, 43.6, 18.6, 14.3. HRMS (ESI) m/z: [M + H]+ calcd for C20H21N2O4S, 385.1222; found, 385.1229.
N-(Tert-butyl)-2-(5,11-dioxo-5,11-dihydro-6H-indeno[1,2-c]isoquinolin-6-yl)acetamide 8
It was synthesized according to procedure C on a 0.15 mmol scale, which afforded 8 (31 mg, 58%) as a red solid; mp: 255–257 °C; Rf = 0.54 (60% EtOAc/petroleum ether). 1H NMR (500 MHz, Chloroform-d) δ 8.72 (d, J = 8.1 Hz, 1H), 8.35 (dd, J = 8.1, 1.3 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.79–7.74 (m, 1H), 7.61 (dd, J = 7.1, 1.2 Hz, 1H), 7.52–7.44 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 6.45 (s, 1H), 5.07 (s, 2H), 1.37 (s, 9H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 190.6, 166.1, 164.2, 155.8, 137.1, 134.5, 134.4, 133.6, 132.5, 131.1, 128.6, 127.4, 123.7, 123.3, 123.2, 123.1, 109.2, 52.0, 49.6, 28.6. HRMS (ESI) m/z: [M + H]+calcd for C22H21N2O3, 361.1552; found, 361.1549.
Acknowledgments
A.D. was supported by the National Institute of Health (NIH) (2R01GM097082-05), the European Lead Factory (IMI) under grant agreement number 115489, and the Qatar National Research Foundation (NPRP6-065-3-012). Moreover, funding was received through ITN “Accelerated Early stage drug dIScovery” (AEGIS, grant agreement No 675555) and COFUND ALERT (grant agreement No 665250), Hartstichting (ESCAPE-HF, 2018B012), and KWF Kankerbestrijding grant (grant agreement No 10504). The authors thank Walid Maho (University of Groningen) and Marcel de Vries (University of Groningen) for their help with HRMS analysis. Q.W. and X.L. acknowledge the China Scholarship Council for supporting.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c01170.
1H and 13C{1H} NMR spectra for compounds 5, 7, and 8 (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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