3-(o-iodophenyl)-quinolinedione compound as well as synthesis method and application thereof

Abstract

The invention discloses a 3-(o-iodophenyl)-quinolinedione compound as well as a synthesis method and application thereof. The structure of the 3-(o-iodophenyl)-quinolinedione compound is shown as a formula I, wherein R1 is an alkyl or aryl substituent, and R2 is an alkyl or aryl substituent. R1 is selected from-CH3,-Et,-nBu,-iPr,-Bn or-Ph; r < 2 > is selected from-H,-CH3,-Et,-nBu or-Bn; ar1 is selected from monosubstituted-CH3,-tBu,-CO2Et,-F,-Cl,-Br,-I or disubstituted-Cl; in the formula, the formula is shown in the description; and Ar2 is selected from monosubstituted-CH3,-tBu,-CO2Me,-COMe,-CF3,-F,-Cl,-Br,-I or disubstituted-Cl. The formula (I) is shown in the description. The invention not only provides a compound with a novel structure, but also realizes rapid and high-selectivity introduction of a plurality of bioactive functional groups from simple precursors to complex polycyclic molecules through modularized reaction site design, greatly expands the chemical space of quinolinone compounds, and has a broad application prospect in the fields of biochemistry, biochemistry, biochemistry, biochemistry, biochemistry, biochemistry, biochemistry, biochemistry, biochemistry, biochemistry, biochemistry, biochemistry, biochemistry and the like. The method has important application value in discovery and optimization of drug lead compounds.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthetic chemistry, and relates to a kind of 3-(2-iodophenyl)-quinoline diketone compound with potential biological activity and a synthetic method and application thereof BACKGROUND

[0002] Quinolinone is a classic drug privileged scaffold, and its core structure 4-quinolinone is a key pharmacophore of quinolone antibacterial drugs (such as ciprofloxacin). In order to overcome the limitations of existing drugs in drug resistance and selectivity, and expand their biological activity spectrum, structural derivatization has become an important research direction.

[0003] Among them, 3-aryl-2,4-quinolinedione as an important structural modifier of 4-quinolinone shows broad prospects in the fields of antiviral, central nervous system and immune regulation, because it can enhance the target force and introduce new pharmacophore sites, so its efficient and universal synthesis method has attracted much attention.

[0004] However, the existing methods for synthesizing 3-aryl-2,4-quinolinedione mostly rely on high temperature, stoichiometric oxidants or pre-functionalization of substrates, and are generally difficult to be compatible with aryl substrates with ortho-substitution, which seriously restricts the rapid construction of structurally diverse derivatives.

[0005] Electrochemical cross-dehydrogenative coupling reaction uses electrons as clean redox reagents, and has the advantages of step economy and high atom economy. Recent studies have shown that iodo-benzene can be selectively functionalized at the ortho C-H bond under electrochemical conditions while retaining iodine. Based on this, there is still a lack of a universal method for directly, mildly and highly regioselectively coupling quinolinone with ortho-substituted iodo-benzene in the prior art. SUMMARY

[0006] The present application aims to overcome the above-mentioned defects of the prior art, and to provide a class of 3-(ortho-iodoaryl)-2,4-quinolinedione compounds with novel structure and easy derivatization, and an electrochemical synthesis method with mild conditions, no pre-functionalization and good functional group compatibility.

[0007] To achieve the above-mentioned purpose, the present application adopts the following technical solutions: 3-(ortho-iodophenyl)-quinolinedione compounds, whose structure is shown in formula I:

[0008] wherein R 1 is an alkyl or aryl substituent, and R 2 is an alkyl or aryl substituent.

[0009] As a preferred, the R 1 is selected from -CH3, -Et, n Bu, -i Pr, -Bn, or -Ph; the R 2 Selected from -H, -CH3, -Et, - n Bu or -Bn; the Ar 1 Selected from monosubstituted -CH3, - t Bu, -CO2Et, -F, -Cl, -Br, -I, or disubstituted -Cl; the Ar 2 Selected from monosubstituted -CH3, - t Bu, -CO2Me, -COMe, -CF3, -F, -Cl, -Br, -I, or disubstituted -Cl.

[0010] The synthesis method of the above-mentioned 3-(2-iodophenyl)-quinolinedione compounds includes the following steps: under air conditions, tetrabutylammonium tetrafluoroborate, hexafluoroisopropanol / trifluoroacetic anhydride mixed solvent, and iodobenzene 2 are added sequentially to a sample vial, and the sample vial is fitted with a cap equipped with a graphite anode and a platinum cathode; electrolysis is carried out under a constant current of 5 mA at room temperature with stirring, followed by the addition of 4-hydroxy-1,3-dimethylquinoline-2(1H)-one 1 for continued electrolysis; after the reaction is completed, the solvent is removed by vacuum distillation, and the crude product is purified by rapid column chromatography to finally obtain the target compound 3-(2-iodophenyl)-quinolinedione compound 3, the reaction formula of which is shown below;

[0011] The three compounds provided by this invention, particularly the aryl iodine structural unit and the ketone carbonyl group, exhibit excellent chemical reactivity and derivatization potential, providing an efficient platform for the rapid construction of structurally diverse quinolinone libraries, specifically in the following ways: 1. Coupling transformation of aryl iodine unit: The aryl iodine can serve as a key reaction site, and through transition metal-catalyzed carbon-carbon coupling reactions (such as Sonogashira coupling), functional groups such as alkyne groups can be efficiently introduced to achieve direct derivatization (e.g., taking 3a as an example, it can be efficiently converted into compound 4).

[0012] 2. Selective Reduction and Subsequent Cyclolation of Ketone Carbonyl Groups: The ketone carbonyl group in a compound can be reduced with high chemoselectivity and high diastereoselectivity under mild conditions (e.g., using LiAlH4) to generate a hydroxyl intermediate with a defined configuration (e.g., compound 5, trans configuration, dr > 20:1, supported by NOE data, using 3a as an example). This hydroxyl intermediate can be further used to efficiently construct polycyclic skeletons via intramolecular Ullmann coupling reactions (e.g., compound 6), demonstrating a convenient pathway for derivatization from linear molecules to complex ring systems.

[0013] 3. Stereoselective functional group transformation of hydroxyl groups: The aforementioned hydroxyl intermediates can serve as stereospecific reaction sites for stereoselective SN1 reactions, thereby efficiently introducing various important functional groups such as fluorine (e.g., compound 7 obtained using BAST reagent) and amino groups (e.g., compound 8 obtained by reacting with acetonitrile under acid catalysis). The relative configuration of compound 8 has been confirmed by single-crystal X-ray diffraction (CCDC 2190325), and the configuration of compound 7 is inferred accordingly.

[0014] Compared with the prior art, the present invention has the following beneficial effects: 1) Green and mild method: The reaction is carried out at room temperature, using electrons as a clean oxidant, without the need for stoichiometric metal oxidants or high-temperature heating, which is in line with the principles of green chemistry.

[0015] 2) Simple and efficient steps: C3-aryl bonds are directly constructed through a one-step electrochemical CDC reaction, which is highly atom-economical and easy to operate.

[0016] 3) Regioselectivity and specificity: The reaction exhibits excellent ortho selectivity, specifically generating 3-(o-iodoaryl) products.

[0017] 4) Broad substrate compatibility: It successfully solves the problem of poor compatibility of traditional methods with ortho-substituted aromatic substrates, and can tolerate a variety of functional groups (such as methyl, ethyl, butyl, ketone carbonyl, ester, trifluoromethyl, halogen).

[0018] 5) Huge derivatization potential: The iodine atom retained in the product can serve as a key synthetic "handle", facilitating rapid and diverse subsequent derivatization through transition metal catalysis and other reactions (such as Sonogashira coupling and Suzuki coupling), providing efficient intermediates for constructing high-value compound libraries.

[0019] In summary, this invention not only provides a novel class of compounds, but also, through its modular reaction site design, enables the rapid and highly selective introduction of compounds ranging from simple precursors to complex polycyclic molecules and various bioactive functional groups, greatly expanding the chemical space of quinolinone compounds and having significant application value in the discovery and optimization of drug lead compounds. Attached Figure Description

[0020] Figure 1 The NOE data spectrum for the relative configuration of the compound is shown in Example 3. Detailed Implementation

[0021] Example 1: Synthesis of Compound 3:

[0022] Under air conditions, tetrabutylammonium tetrafluoroborate (0.1 M, 0.5 mmol, 165 mg), a hexafluoroisopropanol / trifluoroacetic anhydride mixed solvent (20:1, 5.25 mL, v / v), and iodobenzene 2 (0.3 mmol, 61 mg, 34 μL) were sequentially added to 10 mL IKA® ElectraSyn 2.0 sample vials, which were then fitted with dedicated caps equipped with graphite anodes and platinum cathodes. Electrolysis was carried out at a constant current of 5 mA at room temperature with stirring for 6 hours, followed by the addition of 4-hydroxy-1,3-dimethylquinoline-2(1H)-one 1 (0.2 mmol, 38 mg) 1 and continued electrolysis for another 2 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product was purified by rapid column chromatography to finally obtain target compound 3. A total of 39 3-(2-iodophenyl)-quinolinedione compounds were obtained as target compound 3, with a yield as high as 94%. Compounds 3a and 3s were found to have single-crystal supporting structures.

[0023] 3-(2-Iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3a)

[0024] White solid, 72 mg, separation yield 92%.

[0025] 1 H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 7.7, 1.7 Hz, 1H), 7.86 (dd, J =7.8, 1.2 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.54 – 7.44 (m, 2H), 7.31 – 7.21 (m,2H), 7.12 – 7.02 (m, 1H), 3.57 (s, 3H), 1.83 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.0, 172.6, 143.7, 142.9, 140.4, 136.0,130.2, 129.6, 128.5, 128.3, 123.3, 121.3, 115.2, 101.0, 66.1, 30.2, 24.9. HRMS (ESI): calc. for [C 17 H 15 INO2] [M+H] +: 392.0142, found in 392.0142.

[0026] Single crystal CCDC number: 2500589.

[0027] 1,3,6-Trimethylquinoline-2,4(1H,3H)-dione (3b)

[0028] White solid, 73 mg, separation yield 90%. 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 7.5 Hz,1H), 7.54 – 7.43 (m, 3H), 7.18 (d, J = 8.4 Hz, 1H), 7.10 – 7.02 (m, 1H), 3.55 (s, 3H), 2.41 (s, 3H), 1.82 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.3, 172.4, 143.8, 140.7, 140.4, 136.8,133.1, 130.2, 129.5, 128.4, 128.2, 121.1, 115.2, 101.0, 66.1, 30.2, 25.0,20.5. MS (ESI): calc. for [C 18 H 17 INO2] [M+H] + : 406.0296, found in 406.0288.

[0029] 6-tert-butyl-3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3c)

[0030] Pale yellow oily substance, 84 mg, separation yield 94%.

[0031] 1 H NMR (400 MHz, CDCl3) δ8.13 (d, J = 2.5 Hz, 1H), 7.86 (d, J= 7.3 Hz, 1H), 7.74 (dd, J = 8.7, 2.5 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.22 (d, J = 8.7 Hz,1H), 7.08– 7.04 (m, 1H), 3.56 (s, 3H), 1.83 (s, 3H), 1.37 (s, 9H). 13 C NMR(100 MHz, CDCl3) δ195.4, 172.5, 146.4, 143.9, 140.7, 140.3,133.4, 130.2, 129.5, 128.2, 124.8, 120.9, 115.1, 101.0, 66.1, 34.6, 31.3,30.2, 25.0. MS (ESI): calc. for [C 21 H 23 INO2] [M+H] + : 448.0768, found in 448.0760.

[0032] 3-(2-Iodophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylate (3d)

[0033] White solid, 83 mg, separation yield 90%.

[0034] 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.2 Hz, 1H), 8.34 (dd, J = 8.7, 2.2Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.63 – 7.40 (m, 2H), 7.33 (d, J = 8.8 Hz, 1H),7.12 – 7.01 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.58 (s, 3H), 1.82 (s, 3H), 1.39(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 193.9, 172.5, 165.3, 145.9, 143.2, 140.20136.8, 130.1, 130.1, 129.7, 128.2, 125.4, 120.7, 115.3, 100.9, 66.1, 61.4,30.4, 24.7, 14.4. MS (ESI): calc. for [C 20 H 19 INO4 [M+H] + : 464.0353, found in 464.0350.

[0035] 6-Chloro-3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3e)

[0036] White solid, 77 mg, separation yield 91%.

[0037] 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.66 (dd, J = 8.9, 2.6 Hz, 1H), 7.56 – 7.46 (m, 2H), 7.26 (d, J = 8.9 Hz,1H), 7.15 – 7.06 (m, 1H), 3.57 (s, 3H), 1.84 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 193.8, 172.2, 143.3, 141.3, 140.3, 135.7,130.1, 129.7, 129.1, 128.3, 127.9, 122.3, 116.9, 100.9, 66.1, 30.4, 24.8. MS (ESI): calc. for [C 17 H 14 ClINO2] [M+H] + : 425.9752, found in 425.9740.

[0038] 6-Fluoro-3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3f)

[0039] Pale yellow oily substance, 75 mg, separation yield 92%.

[0040] 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.66 (dd, J = 8.9, 2.6 Hz, 1H), 7.56 – 7.46 (m, 2H), 7.26 (d, J = 8.9 Hz,1H), 7.15 – 7.06 (m, 1H), 3.57 (s, 3H), 1.84 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 193.8, 172.2, 143.3, 141.3, 140.3, 135.7,130.1, 129.7, 129.1, 128.3, 127.9, 122.3, 116.9, 100.9, 66.1, 30.4, 24.8. MS (ESI): calc. for [C 17 H 14 INO2] [M+H] + : 410.0048, found in 410.0038.

[0041] 3-(2-Iodophenyl)-1,3,7-Trimethylquinoline-2,4(1H,3H)-dione (3g)

[0042] A light yellow, buttery substance, 66 mg, with a separation yield of 81%.

[0043] 1H NMR(400 MHz, CDCl3) δ 8.04 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.5Hz, 1H), 7.53 – 7.41 (m, 2H), 7.11 – 7.00 (m, 3H), 3.56 (s, 3H), 2.50 (s,3H), 1.82 (s,3H). 13 C NMR(100 MHz, CDCl3) δ 194.7, 172.8, 147.4, 143.8, 142.9, 140.3,130.1, 129.5, 128.6, 128.2, 124.3, 119.2, 115.6, 100.9, 65.9, 30.1, 25.0,22.6. MS (ESI): calc. for [C 18 H 17 INO2] [M+H] + : 406.0299, found in 406.0287.

[0044] 7-Iodo-3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3h)

[0045] White solid, 85 mg, separation yield 82%.

[0046] 1 H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 12.8, 7.9 Hz, 2H), 7.67 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 4.6 Hz, 2H), 7.08 (d, J = 3.9 Hz, 1H), 3.54(s, 3H), 1.81 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.3, 172.4, 143.3, 143.2, 140.3, 132.5,130.1, 129.7, 129.5, 128.3, 124.3, 120.5, 104.1, 100.9, 66.1, 30.3, 24.8. MS (ESI): calc. for [C 17 H 14 I₂NO₂] [M+H] + : 517.9108, found in 517.9096.

[0047] 7-Bromo-3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3i)

[0048] Pale yellow oily substance, 78 mg, separation yield 83%.

[0049] 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 4.1 Hz, 2H), 7.45 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.12 –6.93 (m, 1H), 3.55 (s, 3H), 1.82 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.0, 172.5, 143.7, 143.4, 140.3, 131.0,130.1, 129.9, 129.7, 128.3, 126.5, 120.0, 118.4, 100.9, 66.1, 30.3, 24.9. MS (ESI): calc. for [C 17 H 14 [BrINO2] [M+H] + : 469.9247, found in 469.9244.

[0050] 5,7-Dichloro-3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3j)

[0051] White solid, 69 mg, separation yield 75%.

[0052] 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 6.9 Hz, 2H), 7.30 (d, J = 10.3 Hz, 2H), 7.16 – 7.02 (m, 1H), 3.59 (s, 3H), 1.87 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 191.6, 171.9, 145.4, 142.7, 140.6, 140.6,137.7, 130.0, 129.7, 128.2, 126.5, 117.2, 114.5, 101.1, 66.6, 31.2, 24.1. MS (ESI): calc. for [C 17 H 13 Cl2INO2] [M+H + : 459.9363, found in 459.9350.

[0053] 1-Ethyl-3-(2-iodophenyl)-3-methylquinoline-2,4(1H,3H)-dione (3k)

[0054] Pale yellow oily substance, 60 mg, separation yield 74%.

[0055] 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.71 (t, J = 7.0 Hz, 1H), 7.55 – 7.45 (m, 2H), 7.34 – 7.26 (m, 1H), 7.23(d, J = 7.5 Hz, 1H), 7.14 – 6.97 (m, 1H), 4.33 (dq, J = 14.3, 7.1 Hz, 1H), 4.15(dq, J = 14.2, 7.1 Hz, 1H), 1.85 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.0, 172.1, 143.7, 141.7, 140.3, 136.0,130.2, 129.5, 128.9, 128.2, 123.0, 121.5, 115.1, 101.1, 66.0, 37.8, 24.9,12.0. MS (ESI): calc. for [C 18 H 17 INO2] [M+H] + : 406.0296, found in 406.0293.

[0056] 1-Butyl-3-(2-iodophenyl)-3-methylquinoline-2,4(1H,3H)-dione (3l)

[0057] White solid, 68 mg, separation yield 78%.

[0058] 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.56 – 7.45 (m, 2H), 7.28 (d, J = 1.6 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.12 – 6.99 (m, 1H), 4.55 – 3.15 (m, 2H), 1.84 (s,3H), 1.82 – 1.70 (m, 2H), 1.59 – 1.43 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.0, 172.3, 143.7, 142.1, 140.3, 135.9,130.2, 129.5, 128.8, 128.2, 123.0, 121.4, 115.2, 101.1, 66.1, 42.8, 28.9,25.0, 20.5, 13.9. MS (ESI): calc. for [C 20 H 21 INO2] [M+H] + : 434.0612, found in 434.0608.

[0059] 3-(2-Iodophenyl)-1-isopropyl-3-methylquinoline-2,4(1H,3H)-dione (3m)

[0060] Pale yellow oily substance, 60 mg, separation yield 72%.

[0061] 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 6.0 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.52 – 7.45 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 – 7.00 (m, 1H), 5.07 (br, 1H), 1.81 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H), 1.59 (d, J = 7.0 Hz, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.2, 172.4, 143.8, 142.4, 140.4, 135.6,130.2, 129.5, 129.0, 128.2, 122.9, 122.0, 115.8, 101.2, 66.4, 24.8, 20.0,19.4. MS (ESI): calc. for [C 19 H 19 INO2] [M+H] + : 420.0455, found in 420.0444.

[0062] 1-Benzyl-3-(2-iodophenyl)-3-methylquinoline-2,4(1H,3H)-dione (3n)

[0063] White solid, 78 mg, separation yield 83%.

[0064] 1 H NMR (400 MHz, CDCl3) δ 8.19 – 8.12 (m, 1H), 7.88 (d, J = 7.9 Hz, 1H),7.59 – 7.46 (m, 3H), 7.39 (d, J = 7.1 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.31 –7.24 (m, 1H), 7.23 – 7.16 (m, 2H), 7.12 – 7.02 (m, 1H), 5.65 (d, J = 16.2 Hz, 1H), 5.06 (d, J = 16.2 Hz, 1H), 1.93 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.7, 172.9, 143.5, 142.3, 140.4, 136.5,135.9, 130.2, 129.6, 129.0, 128.6, 128.2, 127.7, 127.1, 123.3, 121.4, 116.1,101.2, 66.3, 47.1, 25.2. MS (ESI): calc. for [C 23 H 19 INO2] [M+H] + : 468.0455, found in 468.0445.

[0065] 3-(2-Iodophenyl)-3-methyl-1-phenylquinoline-2,4(1H,3H)-dione (3o)

[0066] White solid, 76 mg, separation yield 84%.

[0067] 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 6.2 Hz, 1H), 7.87 (d, J= 7.9 Hz,1H), 7.61 – 7.53 (m, 2H), 7.55 – 7.46 (m, 3H), 7.46 (d, J = 6.3 Hz, 2H), 7.32(d, J = 9.6 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 6.6 Hz, 1H), 6.58 (d, J =8.4 Hz, 1H), 2.00 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.9, 172.4, 143.8, 143.3, 140.3, 137.6,135.5, 130.6, 130.3, 130.2, 129.6, 129.2, 129.1, 128.7, 128.3, 128.2, 123.4,120.7, 117.1, 101.3, 66.5, 24.9. MS (ESI): calc. for [C 22 H 17 INO2] [M+H] + : 454.0299, found in 454.0286.

[0068] 1-(cyclopropylmethyl)-3-(2-iodophenyl)-3-methylquinoline-2,4(1H,3H)-dione (3p)

[0069] White solid, 62 mg, separation yield 72%.

[0070] 1 H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 7.7, 1.6 Hz, 1H), 7.86 (d, J = 7.6Hz, 1H), 7.75 – 7.66 (m, 1H), 7.52 – 7.45 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.11 – 7.01 (m, 1H), 4.13 (dd, J= 14.8, 6.7 Hz, 1H), 4.03 (dd, J = 14.8, 7.0 Hz, 1H), 1.84 (s, 3H), 1.30 – 1.23 (m, 1H), 0.67 – 0.34 (m, 4H). 13 C NMR(100 MHz, CDCl3) δ 195.0, 172.7, 143.6, 142.3, 140.3, 135.9,130.1, 129.5, 128.8, 128.2, 123.0, 121.3, 115.5, 101.1, 66.2, 46.7, 25.0,9.3, 4.8, 4.0. MS (ESI): calc. for [C 20 H 19 INO2] [M+H] + : 432.0455, found in 432.0443.

[0071] 3-Ethyl-3-(2-iodophenyl)-1-methylquinoline-2,4(1H,3H)-dione (3q)

[0072] White solid, 61 mg, separation yield 75%.

[0073] 1 H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 7.8, 1.7 Hz, 1H), 7.88 (d, J = 7.8Hz, 1H), 7.75 – 7.66 (m, 1H), 7.52 – 7.45 (m, 2H), 7.28 (s, 1H), 7.26 – 7.20(m, 1H), 7.10 – 7.01 (m, 1H), 3.59 (s, 3H), 2.50 – 2.11 (m, 2H), 1.01 (t, J =7.4 Hz, 3H). 13C NMR(100 MHz, CDCl3) δ 194.8, 171.7, 143.6, 143.2, 140.8, 135.9,130.5, 129.4, 128.0, 127.9, 123.2, 122.8, 115.1, 101.3, 69.9, 32.1, 30.0,9.8. MS (ESI): calc. for [C 18 H 17 INO2] [M+H] + : 406.0299, found in 406.0286.

[0074] 3-Butyl-3-(2-iodophenyl)-1-methylquinoline-2,4(1H,3H)-dione (3r)

[0075] Pale yellow oily substance, 62 mg, separation yield 72%.

[0076] 1 H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 7.88 (d, J = 7.3Hz, 1H), 7.75 – 7.66 (m, 1H), 7.51 – 7.45 (m, 2H), 7.28 (s, 1H), 7.24 (d, J =7.5 Hz, 1H), 7.10 – 7.01 (m, 1H), 3.58 (s, 3H), 2.32 – 2.23 (m, 2H), 1.34 –1.25 (m, 4H), 0.88 – 0.83 (m, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.7, 171.8, 143.7, 143.1, 140.8, 135.9,130.5, 129.4, 128.1, 128.0, 123.2, 122.6, 115.1, 101.3, 69.7, 38.4, 30.0,26.9, 23.2, 13.8. MS (ESI): calc. for [C 20 H 21 INO2] [M+H] +: 434.0612, found in 434.0602.

[0077] 3-Benzyl-3-(2-iodophenyl)-1-methylquinoline-2,4(1H,3H)-dione (3s)

[0078] White solid, 29 mg, separation yield 31%.

[0079] 1 H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 7.8, 1.7 Hz, 1H), 7.88 (dd, J =7.8, 1.4 Hz, 1H), 7.70 (d, J = 9.6 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.39 – 7.30(m, 1H), 7.10 – 7.00 (m, 2H), 6.96 – 6.88 (m, 5H), 6.64 (d, J = 8.4 Hz, 1H), 3.73 (d, J = 11.6 Hz, 1H), 3.60 (d, J = 11.6 Hz, 1H), 3.28 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.7, 171.2, 145.0, 142.6, 140.9, 135.4,133.1, 130.3, 130.1, 129.5, 128.1, 127.5, 127.2, 126.8, 124.3, 122.7, 114.5,100.5, 69.2, 47.8, 29.4. MS (ESI): calc. for [C 23 H 19 INO2] [M+H] + : 468.0455, found in 468.0449.

[0080] Single crystal CCDC number: 2500592.

[0081] 4-Hydroxy-3-(2-iodophenyl)-1-methylquinoline-2(1H)-one (3t)

[0082] White solid, 17 mg, separation yield 23%.

[0083] 1 H NMR(400 MHz, CDCl3) δ 8.11 – 8.00 (m, 2H), 7.70 – 7.61 (m, 1H),7.49 (t, J = 8.1 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.37 – 7.27 (m, 2H), 7.19 –7.10 (m, 1H), 5.66 (s, 1H), 3.75 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 161.7, 155.9, 140.2, 139.9, 136.9, 132.4,131.7, 130.7, 129.4, 124.4, 122.0, 115.4, 115.3, 114.3, 102.3, 29.8. MS (ESI): calc. for [C 16 H 13 INO2] [M+H] + : 377.9986, found in 377.9977.

[0084] (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl-3-(2-iodophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylate (3u)

[0085] White solid, 107 mg, separation yield 93%.

[0086] 1H NMR(400 MHz, CDCl3) δ 8.76 (d, J = 2.1 Hz, 1H), 8.34 (dd, J = 8.7,2.2 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.52 – 7.43 (m, 2H), 7.34 (d, J = 8.8Hz, 1H), 7.12 – 7.00 (m, 1H), 5.02 – 4.90 (m, 1H), 3.58 (s, 3H), 2.10 (d, J =15.4 Hz, 1H), 1.99 – 1.92 (m, 1H), 1.82 (d, J = 4.8 Hz, 3H), 1.73 (d, J =13.3 Hz, 2H), 1.61 – 1.53 (m, 2H), 1.19 – 1.06 (m, 2H), 0.92 (t, J = 5.9 Hz, 7H), 0.79 (d, J = 6.9 Hz, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.0, 172.5, 164.8, 145.7, 143.2, 140.2,136.8, 130.0, 130.0, 129.6, 128.2, 125.7, 120.7, 115.3, 100.9, 75.3, 66.1,47.1, 40.9, 34.2, 31.5, 30.4, 26.4, 24.7, 23.5, 22.1, 20.8, 16.5. MS (ESI): calc. for [C 28 H 33 INO4 [M+H] + : 574.1449, found in 574.1444.

[0087] (1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-3-(2-iodophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-6-carboxylate (3v)

[0088] White solid, 102 mg, separation yield 86%.

[0089] 1H NMR(400 MHz, CDCl3) δ 8.77 (d, J = 2.1 Hz, 1H), 8.34 (dd, J = 8.7,2.2 Hz, 1H), 7.85 – 7.78 (m, 1H), 7.52 – 7.41 (m, 2H), 7.35 (d, J = 8.8 Hz,1H), 7.11 – 6.98 (m, 1H), 5.18 – 5.09 (m, 1H), 3.57 (s, 3H), 2.52 – 2.40 (m,1H), 2.12 (ddd, J = 13.2, 9.3, 4.3 Hz, 1H), 1.82 (s, 3H), 1.75 (dq, J = 18.2,4.3 Hz, 2H), 1.33 (d, J = 46.5 Hz, 3H), 0.95 (s, 3H), 0.92 – 0.87 (m, 6H). 13 C NMR(100 MHz, CDCl3) δ 193.7, 172.3, 165.2, 145.4, 142.8, 139.9,136.5, 129.8, 129.6, 129.4, 127.9, 125.5, 120.4, 115.2, 100.6, 80.8, 65.8,48.9, 47.7, 44.7, 36.6, 30.2, 27.8, 27.1, 24.4, 19.5, 18.7, 13.4. MS (ESI): calc. for [C 28 H 30 [INNaO4] [M+Na] + :594.1112, found in594.1106.

[0090] 3-(2-Iodo-5-methylphenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3w)

[0091] Pale yellow oily substance, 41 mg, separation yield 50%.

[0092] 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 6.1 Hz, 1H), 7.73 (d, J= 8.0 Hz,2H), 7.35 – 7.26 (m, 3H), 6.90 (d, J = 7.9 Hz, 1H), 3.59 (s, 3H), 2.40 (s, 3H), 1.84 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.1, 172.7, 143.3, 142.9, 140.1, 138.1,136.0, 131.3, 130.6, 128.5, 123.2, 121.3, 115.2, 96.8, 65.9, 30.2, 24.9,21.5. MS (ESI): calc. for [C 18 H 17 INO2] [M+H] + : 406.0299, found in 406.0289.

[0093] 3-(5-tert-butyl-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3x)

[0094] White solid, 59 mg, separation yield 66%.

[0095] 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 6.1 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J =7.4 Hz, 1H), 7.13 – 7.06 (m, 1H), 3.57 (s, 3H), 1.84 (s, 3H), 1.36 (s, 9H). 13C NMR(100 MHz, CDCl3) δ 195.2, 172.7, 151.1, 143.0, 139.8, 135.9,128.5, 127.4, 127.1, 126.1, 123.2, 121.3, 115.2, 97.2, 66.2, 35.0, 31.4,30.2, 24.8. MS (ESI): calc. for [C 21 H 23 INO2] [M+H] + : 448.0768, found in 448.0756.

[0096] 3-(5-bromo-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3y)

[0097] White oily substance, 73 mg, separation yield 78%.

[0098] 1 H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 7.8, 1.7 Hz, 1H), 7.73 (dd, J =15.2, 8.5 Hz, 2H), 7.61 (d, J = 2.3 Hz, 1H), 7.34 – 7.26 (m, 2H), 7.23 (dd, J =8.3, 2.3 Hz, 1H), 3.59 (s, 3H), 1.84 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.5, 172.0, 145.8, 142.7, 141.5, 136.2,133.6, 132.7, 128.6, 123.4, 123.1, 121.1, 115.3, 98.9, 66.0, 30.3, 24.9. MS (ESI): calc. for [C 17 H 14 [BrINO2] [M+H] + : 469.9247, found in 469.9239.

[0099] 3-(5-Chloro-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z)

[0100] Pale yellow oily substance, 56 mg, separation yield 66%.

[0101] 1 H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 7.8, 1.7 Hz, 1H), 7.81 – 7.70 (m,2H), 7.48 (d, J = 2.4 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.09 (dd, J = 8.3, 2.5 Hz,1H), 3.60 (s, 3H), 1.85 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 194.5, 172.0, 145.6, 142.8, 141.2, 136.2, 135.0, 130.8, 129.7, 128.6, 123.4, 121.2, 115.3, 98.0, 66.0, 30.3, 24.9. MS (ESI): calc. for [C 17 H 14 ClINO2] [M+H] + : 425.9752, found in 425.9739.

[0102] 3-(5-fluoro-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z1)

[0103] White oily substance, 49 mg, 60% isolated product.

[0104] 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 9.5 Hz, 1H), 7.81 (dd, J= 8.6, 5.7Hz, 1H), 7.78 – 7.69 (m, 1H), 7.36 – 7.26 (m, 3H), 6.90 – 6.80 (m, 1H), 3.60 (s, 3H), 1.84 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.5, 172.0, 164.4, 161.9, 146.3, 146.2,142.8, 141.4, 141.3, 136.2, 128.6, 123.4, 121.2, 118.6, 118.4, 116.8, 116.6,115.3, 93.7, 93.6, 65.9, 30.2, 24.9. MS (ESI): calc. for [C 17 H 14 FINO2] [M+H] + : 410.0048, found in 410.0039. 19 F NMR (377 MHz, CDCl3) δ -113.54.

[0105] 3-(2-Iodo-5-(trifluoromethyl)phenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z2)

[0106] White oily substance, 24 mg, separation yield 26%.

[0107] 1 H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 7.8, 1.7 Hz, 1H), 8.01 (d, J = 8.1Hz, 1H), 7.79 – 7.67 (m, 2H), 7.37 – 7.26 (m, 3H), 3.59 (s, 3H), 1.89 (s, 3H). 13C NMR(100 MHz, CDCl3) δ 194.4, 171.9, 144.9, 142.8, 140.9, 136.3,130.9, 130.6, 128.6, 126.8, 126.7, 126.2, 126.2, 123.5, 122.8, 121.1, 115.3,105.3, 66.2, 30.3, 24.9. 19 F NMR (377 MHz, CDCl3) δ -62.72. MS (ESI): calc. for [C 18 H 14 F3INO2] [M+H] + : 460.0016, found in 460.0013.

[0108] 3-(5-acetyl-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z3)

[0109] White solid, 26 mg, separation yield 30%.

[0110] 1 H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 7.8, 1.7 Hz, 1H), 8.07 (d, J = 2.1Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.77 – 7.68 (m, 1H), 7.61 (dd, J = 8.1, 2.1Hz, 1H), 7.33 – 7.25 (m, 2H), 3.58 (s, 3H), 2.62 (s, 3H), 1.91 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 197.3, 194.7, 172.2, 144.5, 142.8, 140.8,136.8, 136.2, 129.5, 129.3, 128.6, 123.4, 121.1, 115.3, 107.7, 66.2, 30.3,26.7, 25.0. MS (ESI): calc. for [C19 H 17 INO3 [M+H] + : 434.0248, found in 434.0235.

[0111] 3-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)-4-iodobenzoate (3z4)

[0112] Colorless oily substance, 20 mg, separation yield 22%.

[0113] 1 H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 4.8, 1.8 Hz, 2H), 7.96 (d, J = 8.1Hz, 1H), 7.72 (t, J = 7.3 Hz, 2H), 7.33 – 7.23 (m, 2H), 3.94 (s, 3H), 3.58 (s, 3H), 1.90 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.6, 172.1, 166.7, 144.3, 142.8, 140.6,136.2, 131.0, 130.3, 130.2, 128.5, 123.4, 121.1, 115.3, 107.3, 66.2, 52.5,30.2, 25.0. MS (ESI): calc. for [C 19 H 17 INO4 [M+H] + : 450.0124, found in 450.0188.

[0114] 3-(2-Iodo-4-methylphenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z5)

[0115] Pale yellow oily substance, 29 mg, separation yield 36%.

[0116] 1 H NMR (400 MHz, CDCl3) δ 8.14 (dd, J= 7.8, 1.7 Hz, 1H), 7.69 (s, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.8 Hz, 3H), 3.56 (s, 3H), 2.31 (s, 3H), 1.80 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.2, 172.7, 142.9, 141.0, 140.7, 139.6,135.9, 129.7, 129.0, 128.5, 123.2, 121.3, 115.2, 100.7, 65.7, 30.2, 25.0,20.6. MS (ESI): calc. for [C 18 H 17 INO2] [M+H] + : 406.0299, found in 406.0289.

[0117] 3-(4-bromo-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z6)

[0118] Pale yellow oily substance, 62 mg, separation yield 66%.

[0119] 1 H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 7.8, 1.7 Hz, 1H), 8.00 (d, J = 2.0Hz, 1H), 7.76 – 7.67 (m, 1H), 7.60 (dd, J = 8.4, 2.1 Hz, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.32 – 7.24 (m, 2H), 3.57 (s, 3H), 1.81 (s, 3H). 13C NMR(100 MHz, CDCl3) δ 194.6, 172.1, 142.9, 142.8, 142.3, 136.2,131.3, 131.2, 128.6, 123.4, 122.4, 121.1, 115.3, 101.2, 65.8, 30.3, 25.0. MS (ESI): calc. for [C 17 H 14 [BrINO2] [M+H] + : 469.9247, found in 469.9239.

[0120] 3-(2-Iodo-3-methylphenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z7)

[0121] Pale yellow oily substance, 41 mg, separation yield 51%.

[0122] 1 H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 7.7, 1.7 Hz, 1H), 7.75 – 7.66 (m,1H), 7.37 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 3H), 7.24 (s, 1H), 3.57 (s, 3H), 2.45 (s, 3H), 1.82 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 195.0, 172.8, 144.5, 143.1, 142.8, 135.9,129.6, 128.5, 128.2, 127.7, 123.2, 121.5, 115.2, 108.5, 66.9, 30.4, 30.2,25.4. MS (ESI): calc. for [C 18 H 17 INO2] [M+H] + : 406.0296, found in 406.0291.

[0123] 3-(2,3-Diiodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z8)

[0124] White solid, 41 mg, separation yield 40%.

[0125] 1 H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 7.7, 1.7 Hz, 1H), 7.91 (dd, J =7.9, 1.4 Hz, 1H), 7.71 (t, J = 7.0 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H), 7.29 – 7.23(m, 2H), 7.19 (t, J = 7.8 Hz, 1H), 3.57 (s, 3H), 1.78 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.5, 172.3, 146.3, 142.7, 139.2, 136.0,129.4, 129.3, 128.6, 123.3, 121.4, 115.2, 115.2, 111.6, 68.6, 30.2, 25.7. MS (ESI): calc. for [C 17 H 14 I₂NO₂] [M+H] + : 517.9108, found in 517.9110.

[0126] 3-(3-bromo-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z9)

[0127] White solid, 70 mg, separation yield 75%.

[0128] 1 H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 7.8, 1.7 Hz, 1H), 7.71 (t, J = 7.8Hz, 1H), 7.65 (d, J= 6.1 Hz, 1H), 7.40 (d, J = 6.2 Hz, 1H), 7.34 (t, J = 7.8 Hz,1H), 7.30 – 7.23 (m, 2H), 3.57 (s, 3H), 1.81 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.5, 172.2, 147.0, 142.7, 136.1, 132.3,132.2, 129.4, 128.6, 128.6, 123.3, 121.3, 115.3, 108.9, 67.7, 30.2, 25.5. MS (ESI): calc. for [C 17 H 14 [BrINO2] [M+H] + : 469.9247, found in 469.9237.

[0129] 3-(3-Chloro-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z10)

[0130] White solid, 57 mg, separation yield 67%.

[0131] 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.8 Hz, 1H), 7.75 – 7.65 (m, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.30– 7.21 (m, 2H), 3.57 (s, 3H), 1.82 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.5, 172.2, 146.8, 142.7, 140.3, 136.1,129.2, 128.8, 128.5, 128.1, 123.3, 121.3, 115.3, 106.0, 67.2, 30.2, 25.4. MS (ESI): calc. for [C 17 H 14 ClINO2] [M+H] + : 425.9752, found in 425.9741.

[0132] 3-(3-fluoro-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z11)

[0133] Pale yellow oily substance, 52 mg, separation yield 63%.

[0134] 1 H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 7.8, 1.7 Hz, 1H), 7.77 – 7.68 (m,1H), 7.50 – 7.40 (m, 1H), 7.33 – 7.24 (m, 3H), 7.08 (t, J = 7.2 Hz, 1H), 3.57(s, 3H), 1.85 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 194.7, 172.2, 163.3, 160.9, 146.2, 142.8,136.2, 129.9, 129.9, 128.6, 125.8, 125.7, 123.4, 121.1, 115.3, 115.3, 115.1,88.9, 88.6, 66.0, 66.0, 30.2, 25.2. 19 F NMR(377 MHz, CDCl3) δ -87.63.MS (ESI): calc. for [C 17 H 14 FINO2] [M+H] + : 410.0048, found in 410.0037.

[0135] 3-(3,5-Dichloro-2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z12)

[0136] Pale yellow oily substance, 59 mg, separation yield 64%.

[0137] 1 H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 7.8, 1.7 Hz, 1H), 7.72 – 7.57 (m,1H), 7.52 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 3.50 (s, 3H), 1.74 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 194.3, 172.0, 145.4, 142.6, 138.5, 136.2, 132.0, 130.0, 128.8, 128.6, 123.5, 121.2, 115.3, 107.4, 67.2, 30.3, 25.4. MS (ESI): calc. for [C 17 H 13 Cl2INO2] [M+H + : 459.9363, found in459.9355.

[0138] 3-(2,4-Dichloro-6-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3z13)

[0139] Pale yellow oily substance, 33 mg, separation yield 36%.

[0140] 1 H NMR (400 MHz, CDCl3,353 K) δ 8.06 (s, 1H), 8.01 (dd, J = 7.8, 1.7 Hz, 1H), 7.80 (ddd, J = 8.8, 7.3, 1.7 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.51 (d, J =7.6 Hz, 1H), 7.35 – 7.28 (m, 1H), 3.50 (s, 3H), 2.04 (s, 3H). 13C NMR(100 MHz, CDCl3) δ 193.0, 171.1, 141.7, 139.6, 138.1, 135.8,135.3, 132.5, 130.6, 127.0, 122.5, 119.7, 115.7, 29.5, 26.7. MS (ESI): calc. for [C 17 H 13 Cl2INO2] [M+H + : 459.9363, found in459.9355.

[0141] Example 2: Application Experiment of 3-(o-iodophenyl)-quinolinedione Compounds: Coupling transformation of aryl iodine units. Aryl iodine can serve as a key reaction site, efficiently introducing alkynyl functional groups through transition metal-catalyzed carbon-carbon coupling reactions, achieving direct derivatization to obtain compound 4:

[0142] 3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione (3a) (78.0 mg, 0.20 mmol), phenylacetylene (82 mg, 0.80 mmol), cuprous iodide (3.9 mg, 0.020 mmol), and tetra(triphenylphosphine)palladium (23 mg, 0.020 mmol) were dissolved in a tetrahydrofuran / triethylamine mixed solvent (1:1, total volume 2.0 mL). The reaction mixture was stirred at 80°C for 24 hours under nitrogen protection in a sealed tube. After the reaction solution was cooled to room temperature, the solvent was removed by vacuum distillation. The crude residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to give the target product 1,3-dimethyl-3-(2-(phenylethynyl)phenyl)quinoline-2,4(1H,3H)-dione 4 (71 mg, yield 97%), as a yellow oil. 1 HNMR(400 MHz, CDCl3) δ 8.17 (dd, J = 7.7, 1.7 Hz, 1H), 7.63 – 7.44 (m, 4H), 7.35 (td, J = 7.6, 1.2 Hz, 1H), 7.23 – 7.11 (m, 2H), 7.02 (t, J = 7.8 Hz,2H), 6.93 (d, J = 7.5 Hz, 1H), 6.71 – 6.62 (m, 2H), 3.31 (s, 3H), 1.86 (s,3H). 13C NMR(100 MHz, CDCl3) δ 195.8, 173.5, 143.4, 143.2, 135.6, 132.8, 131.0,128.7, 128.5, 128.4, 127.9, 127.7, 127.7, 122.9, 122.4, 122.2, 120.8, 115.1,95.3, 88.0, 61.9, 29.9, 24.0.MS (ESI): calc. for [C 25 H 20 NO2] [M+H] + : 366.1488, found in 366.1486.

[0143] Example 3: Application Experiment of 3-(o-iodophenyl)-quinolinidone Compounds: The ketone carbonyl group in the compound can be reduced with high chemoselectivity and high diastereoselectivity under mild conditions (e.g., using LiAlH4) to generate a hydroxyl intermediate with a defined configuration. Using compound 3a, compound 5 is derivatized, with a trans configuration and dr > 20:1, supported by NOE data, such as... Figure 1 As shown.

[0144]

[0145] Under nitrogen atmosphere, 3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione 3a (196 mg, 0.5 mmol) and tetrahydrofuran (5.0 mL) were added to a dry 25 mL Shrek flask equipped with a magnetic stir bar and a rubber septum. The solution was stirred at 0°C for 10 minutes, followed by the slow addition of lithium aluminum hydride (38 mg, 1.0 mmol). After the reaction was monitored by TLC, the reaction was quenched dropwise with saturated ammonium chloride solution in an ice bath until no more bubbles were generated. The resulting suspension was filtered through diatomaceous earth and washed with ethyl acetate (10 mL × 3 times). The filtrate was then extracted with ethyl acetate (3 × 20.0 mL), the organic layers were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain the target alcohol compound (3R)-4-hydroxy-3-(2-iodophenyl)-1,3-dimethyl-3,4-dihydroquinoline-2(1H)-one (142 mg, yield 72%), which was a yellow oil.

[0146] 1H NMR(400 MHz, CDCl3) δ 8.02 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.0Hz, 1H), 7.44 – 7.34 (m, 3H), 7.17 – 7.06 (m, 2H), 6.95 (t, J = 7.5 Hz, 1H), 4.53 (s, 1H), 3.49 (s, 3H), 2.04 (br, 1H), 1.58 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 170.7, 142.8, 142.7, 138.6, 130.0, 129.9,129.7, 128.8, 128.1, 125.1, 123.3, 114.7, 100.8, 76.9, 54.3, 30.5, 25.0. MS (ESI): calc. for [C 17 H 17 INO2] [M+H] + : 394.0298, found in 394.0294.

[0147] Example 4: Application Experiment of 3-(o-iodophenyl)-quinolinidone Compounds: The ketone carbonyl group in the compound can be reduced with high chemoselectivity and high diastereoselectivity under mild conditions to generate a hydroxyl intermediate with a defined configuration. This hydroxyl intermediate can be further used to efficiently construct polycyclic skeletal compound 6 via intramolecular Ullmann coupling reaction, demonstrating a convenient pathway for derivatization from linear molecules to complex ring systems.

[0148]

[0149] Under nitrogen protection, 4-hydroxy-3-(2-iodophenyl)-1,3-dimethyl-3,4-dihydroquinoline-2(1H)-one 5 (79.0 mg, 0.2 mmol), cuprous iodide (3.9 mg, 0.02 mmol), 1,10-phenanthroline (7.2 mg, 0.04 mmol), and cesium carbonate (130 mg, 0.4 mmol) were dissolved in toluene (2.0 mL) and reacted in a sealed tube at 110°C with stirring for 20 hours. After the reaction solution cooled to room temperature, water (10 mL) was added, and the mixture was extracted with dichloromethane (3 × 20.0 mL). The combined organic layers were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to obtain the target product (6aR)-5,6a-dimethyl-6a,11a-dihydrobenzofurano[3,2-c]quinoline-6(5H)-one (48 mg, 90% yield), which was a yellow oil.

[0150] 1 H NMR(400 MHz, CDCl3) δ 7.57 (d, J = 9.0 Hz, 2H), 7.50 – 7.41 (m,1H), 7.20 (t, J = 7.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 7.01 (t, J = 7.5 Hz,1H), 6.80 (d, J = 7.9 Hz, 1H), 5.33 (s, 1H), 3.36 (s, 3H), 1.66 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 170.6, 158.2, 139.8, 131.7, 131.3, 131.0,129.3, 125.9, 123.5, 121.8, 118.7, 114.9, 109.6, 87.2, 50.5, 30.0, 23.0. MS (ESI): calc. for [C 17 H 16 INO2] [M+H] + : 266.1175, found in 266.1173.

[0151] Example 5: Application experiment of 3-(o-iodophenyl)-quinolinedione compounds: The above-mentioned hydroxyl intermediate can be used as a stereospecific reaction site to carry out a stereoselective SN1 reaction, thereby efficiently introducing fluorine. Compound 7 was obtained using BAST reagent.

[0152]

[0153] Under nitrogen protection, 79.0 mg (0.2 mmol) of 4-hydroxy-3-(2-iodophenyl)-1,3-dimethyl-3,4-dihydroquinoline-2(1H)-one and bis(2-methoxyethyl)aminosulfur trifluoride (66 mg, 0.3 mmol) were dissolved in 2.0 mL of dichloromethane and reacted with the solution in a sealed tube at 0°C for 3 hours. After the reaction was completed, the reaction was quenched dropwise with saturated ammonium chloride solution in an ice bath until no more bubbles were generated. Saturated brine (10 mL) was added, and the mixture was extracted with dichloromethane (3 × 10.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the target product (3S,4S)-4-fluoro-3-(2-iodophenyl)-1,3-dimethyl-3,4-dihydroquinoline-2(1H)-one 7 (65 mg, yield 82%), which was a yellow oil.

[0154]

[0155] 1 H NMR(400 MHz, CDCl3) δ 8.00 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.4Hz, 1H), 7.44 – 7.34 (m, 3H), 7.16 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.2 Hz,1H), 6.99 (t, J = 7.4 Hz, 1H), 6.59 (d, J = 50.6 Hz, 1H), 3.44 (s, 3H), 1.66(s, 3H). 13 C NMR(100 MHz, CDCl3) δ 170.5, 170.4, 142.5, 142.1, 130.1, 129.8,129.4, 128.2, 126.1, 123.5, 123.3, 123.2, 114.3, 91.2, 90.0, 54.7, 54.6,30.3, 17.1, 17.1. MS (ESI): calc. for [C 17 H 16 INO2] [M+H] + : 266.1175, found in 266.1173.

[0156] Example 6: Application experiment of 3-(o-iodophenyl)-quinolinedione compounds: The above-mentioned hydroxyl intermediate can be used as a stereospecific reaction site to carry out a stereoselective SN1 reaction, thereby efficiently introducing an amino group. Under acid catalysis, it reacts with acetonitrile to obtain compound 8. The relative configuration of compound 8 has been confirmed by single-crystal X-ray diffraction (CCDC 2190325).

[0157]

[0158] Under nitrogen protection, 4-hydroxy-3-(2-iodophenyl)-1,3-dimethyl-3,4-dihydroquinoline-2(1H)-one 5 (79.0 mg, 0.2 mmol) was dissolved in concentrated sulfuric acid (39 mg, 0.4 mmol) in acetonitrile (2.0 mL), and the mixture was stirred at 80°C for 1 hour in a sealed tube. After cooling the reaction solution to room temperature, the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain the target product N-((3R,4S)-3-(2-iodophenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-yl)acetamide 8 (62 mg, yield 71%), a white solid.

[0159] 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.9Hz, 2H), 7.19 (d, J = 7.5 Hz, 2H), 7.04 (t, J = 7.9 Hz, 2H), 6.89 (t, J = 7.7Hz, 1H), 6.67 (s, 1H), 3.44 (s, 3H), 1.83 (s, 3H), 1.47 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 171.8, 170.1, 142.7, 141.9, 138.9, 129.0,128.8, 127.5, 125.8, 125.3, 123.8, 123.4, 114.8, 114.6, 54.0, 50.7, 30.5,22.9, 17.6. MS (ESI): calc. for [C 19 H 20 IN₂O₂] [M+H] + : 435.0564, found in 435.0560. Single crystal CCDC:2190325.

[0160] In summary, 3-(2-iodophenyl)-1,3-dimethylquinoline-2,4(1H,3H)-dione 3a, containing both carbonyl and iodine atoms, serves as a key chemical handle, enabling the construction of quinoline ketones through coupling, selective reduction, cyclization, fluorination, and amination, as shown in the following formula: .

Claims

1,3-(o-iodophenyl)-quinolinidone compounds, the structure of which is shown in Formula I, wherein R 1 R is an alkyl or aryl substituent. 2 It is an alkyl or aryl substituent. 。 2. The 3-(o-iodophenyl)-quinolinedione compound as described in claim 1, characterized in that, The R 1 Selected from -CH3, -Et, - n Bu、- i Pr, -Bn, or -Ph; the R 2 Selected from -H, -CH3, -Et, - n Bu or -Bn; the Ar 1 Selected from monosubstituted -CH3, - t Bu, -CO2Et, -F, -Cl, -Br, -I, or disubstituted -Cl; the Ar 2 Selected from monosubstituted -CH3, - t Bu, -CO2Me, -COMe, -CF3, -F, -Cl, -Br, -I, or disubstituted -Cl.

3. The method for synthesizing the 3-(2-iodophenyl)-quinolinedione compound according to claim 1, characterized in that... The process includes the following steps: Under air conditions, tetrabutylammonium tetrafluoroborate, a mixed solvent of hexafluoroisopropanol / trifluoroacetic anhydride, and iodobenzene 2 are sequentially added to a sample vial, and the vial is fitted with a cap equipped with a graphite anode and a platinum cathode; electrolysis is carried out at a constant current of 5 mA at room temperature with stirring, followed by the addition of 4-hydroxy-1,3-dimethylquinoline-2(1H)-one 1 for further electrolysis; after the reaction is completed, the solvent is removed by vacuum distillation, and the crude product is purified by rapid column chromatography to finally obtain the target compound 3-(2-iodophenyl)-quinolinedione compound 3, the reaction formula of which is shown below: 。 4. The use of the 3-(2-iodophenyl)-quinolinedione compound of claim 1 in derivatization.

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