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DOI: 10.1055/s-0042-1751406
A Novel Ring-Opening/Ring-Closing Cascade Reaction Selectively Induced by Aliphatic Primary Amine Using Phenolic Hydroxyl as a Traceless Directing Group
This work was supported by the National Natural Science Foundation of China (Nos. 21662046 and 21202142), the Yunnan Local Colleges Research Projects of China (No. 202101BA070001-049), and the Program of Innovative Research Team (in science and technology) in University of Yunnan Province and Scientific and Technological Innovation Team for Green Catalysis and Energy Material in Yunnan Institutions of Higher Learning.
Abstract
An interesting ring-closing/ring-opening cascade reaction selectively induced by aliphatic primary amine for the synthesis of functionalized aminomaleimides is described. This work features phenolic hydroxyl as a traceless directing group that forms a critical six-membered intermediate and then a lactone ammonolysis/intramolecular amidation sequence. This two-step, one-pot practical protocol has broad substrate scope (39 examples) and delivers structurally diverse aminomaleimides in good to excellent yields.
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Key words
aminomaleimides - ring-closing/ring-opening reaction - aliphatic primary amines - phenolic hydroxyl - directing groupAminomaleimides are important building blocks for synthetic organic chemistry,[1] and they are frequently found in biologically active molecules,[2] such as sulfanilamides, anti-infective agents, and paliperidone fragment derivatives (Scheme [1a]). Because of the multifunctional properties of these architectures, great attention has been devoted to developing efficient protocols for the construction of this scaffold in recent decades. Until now, general approaches to the construction of aminomaleimides have mainly included: (i) dimethyl but-2-ynedioate as a type of Michael receptor to react with amines through an aza-Michael addition/ester ammonolysis sequence (Scheme [1b], route 1);[3] (ii) aminolysis and cyclization of halogen substituted maleic anhydrides (Scheme [1b], route 2);[4] (iii) direct amination and oxidation of maleimides (Scheme [1b], route 3).[5] However, despite these advances, the synthetic methods mentioned above frequently have limited substrate scope, are multistep processes, and deliver low yields. Consequently, the development of a concise and practical route to the preparation of functionalized aminomaleimides is still highly desired, yet it remains a formidable challenge.
Phenolic hydroxyl, as a traceless directing group, has proved to be a versatile functional group and it is widely used in organic synthesis, as for example in Gevorgyan and Jiang’s work.[6] In addition, ring-opening/ring-closing cascade reactions induced by primary amines is an interesting process. Recently, Zhou reported a selective oxidative cleavage of 3-methylindoles with primary amines involving an oxygenation/nitrogenation/ring-opening/recyclization sequence to provide a broad range of quinazolinones (Scheme [1c]).[7]
As inspired by these elegant works, as well as our continuous interest in the field of nitrogen-containing heterocycles,[8] we envisaged that phenolic hydroxyl could be used as a traceless directing group to participate in a cyclization process to form a six-membered intermediate that then reacts with aliphatic primary amine to give aminomaleimides. Indeed, this assumption was confirmed by our experiments, and we herein report a feasible route in which a novel ring-opening/ring-closing cascade reaction, selectively induced by aliphatic primary amine using phenolic hydroxyl as a traceless directing group, is used to produce diverse aminomaleimides in good to high yields.
At the outset, the optimization of reaction conditions for this three-component cascade process involving the readily available materials 2-aminophenol 1a, diethyl acetylene dicarboxylate 2a and benzylamine 3a as model substrates was investigated. Various reaction parameters were investigated, including inorganic or organic base catalysts, reaction medium, and reaction temperature (for details see the Supporting Information). To our delight, aminomaleimide 4a was generated with good yield (40–82%) in this ring-opening/ring-closing cascade reaction when water was used as reaction medium at ambient temperature (Table [1], entries 1–9). Interestingly, the yield of product 4a was improved to 85% in the absence of any catalyst, yet increasing the temperature was detrimental to this reaction (entries 10 and 11). In an effort to increase the solubility of reactants, mixed solvents (EtOH/H2O) were used to test this transformation. The experimental results indicated that different ratios of mixed solvents had a significant effect on the reaction; more ethanol in the medium was adverse to this reaction (entries 12–16). Ultimately, product 4a was obtained in 90% yield in an environmentally benign medium (EtOH/H2O, 1:10 v/v) at ambient temperature (entry 12).
a All reactions were performed with 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.1 mmol) and catalyst (25 mol%) in 3 mL solvent.
b Isolated yield based on 4a.
c Reaction temperature 50 °C.
Having established the optimal reaction conditions, we turned our attention to evaluating the scope of the substrates, as shown in Scheme [2]. Firstly, when diethyl acetylene dicarboxylate 2a was replaced with dimethyl acetylene dicarboxylate 2b, the desired product 4a was also produced with satisfactory yield in this transformation. To our delight, this ring-opening/ring-closing cascade reaction showed excellent functional group tolerance for a wide range of primary amines, providing the desired aminomaleimides in good to excellent yields. Substitutes on the para/ortho-site of the aromatic nucleus, including electron-donating group (Me), electron-withdrawing groups (Cl, Br) or even 1-(2-naphthyl)methylamine, were all suitable for this transformation, delivering products 4b–f in 73–86% yield. Furthermore, extending the carbon chain of the primary amine, such as 2-phenylethanamine and 3-phenylpropylamine, also suited this cascade reaction (4g–h). Remarkably, 3-pyridylmethanamine, 2-furanmethanamine, 2-thiophenemethylamine and tryptamine, as representative heterocyclic aliphatic amines, were all compatible with this reaction, affording products 4i–l in 69–85% yield. In addition, a wide range of aliphatic primary amines were appropriate for this reaction to prepare structurally diverse aminomaleimides 4m–z in 73–93% yield, including linear, branched, and even cyclic substrates. Moreover, this ring-opening/ring-closing reaction can be scaled up to 10 mmol scale, providing product 4a in satisfactory yield. The relative configuration of compound 4e was determined by X-ray diffraction analysis (CCDC 2210943).[9]
Next, the compatibility of this cascade reaction protocol with various 2-aminophenols 1 were examined, as shown in Scheme [3]. Variations of substituents at the para/meta/ortho-position on the aromatic ring were examined, including electron-donating (Me, tBu, OMe) or electron-withdrawing (CO2Me, Cl, Br, CN) groups, providing the corresponding products 5a–k in 73–91% yield (Scheme [3]). Furthermore, 1-(2-naphthyl)methanamine were well tolerated in this transformation, resulting in product 5l and 5m in 68–77% yield, respectively. Notably, aniline and secondary amine proved to be inappropriate substrates in this reaction due to the reaction activity and steric hindrance.
To further illustrate the potential utility of this methodology, the transformation of product 4a was conducted, as shown in Scheme [4]. The reaction between 4a and ethyl propiolate catalyzed by DABCO occurred smoothly in CH3CN to afford the corresponding product 4aa in 81% yield.
To probe the reaction mechanism of this ring-opening/ring-closing process, control experiments on this reaction were conducted (Scheme [5]). First, the key intermediate 6 was generated via an aza-Michael addition/intramolecular ester exchange sequence between 1a and 2a under standard conditions in 5 min (Scheme [5a]). Subsequently, the intermediate 6 was induced by benzylamine 3a to produce ring-opening compound 7 via a lactone ammonolysis, and finally product 4a underwent an electrophilic selective process (Scheme [5b]). In addition, when pyrocatechol 8, benzene-1,2-diamine 10, and 2-aminobenzenethiol 12 were used as the homologous nucleophiles with 2a under standard conditions, the corresponding cyclization intermediates 11 and 13 were obtained. When aniline 14 was used instead of 2-aminophenol to perform the reaction, the main product diethyl 2-(phenylamino)maleate 15 was obtained. However, compounds 11, 13, and 15 did not react further with benzylamine 3a (Scheme [5c–f]).
Subsequently, based on the above experimental results and on relevant reports,[7] a plausible mechanism to rationalize the ring-opening/ring-closing process was developed, as described in Scheme [6]. Initially, the key intermediate 6 is generated via an aza-Michael addition/1,3-H shift/intramolecular ester exchange sequence between 1a and 2a under standard conditions. Subsequently, benzylamine 3a attacks the carbonyl group of lactone, resulting in lactone ammonolysis to produce ring-opening intermediate 7. Intermediate 7 undergoes an intramolecular amidation to eliminate a molecule of ethanol, and finally provide the ring-closed product 4a.
In summary, we described an interesting ring-opening/ring-closing cascade reaction induced by aliphatic primary amine, providing a facile and flexible route to structurally diverse aminomaleimides. This work features phenolic hydroxyl, as a traceless directing group, which formed a critical six-membered intermediate and then underwent a lactone ammonolysis/intramolecular amidation sequence. This two-step, one-pot and directly practical protocol has a broad substrate scope and delivers good to excellent yields. Further applications of these functionalized molecules are under investigation in our laboratory.
All reagents were obtained from commercial suppliers and used without further purification. All compounds were characterized by full spectroscopic data. The 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded with a Bruker Avance III 400 MHz (1H NMR: 400 MHz, 13C NMR: 100 MHz). Chemical shifts reported in parts per million relative to CDCl3 (1H NMR; 7.28 ppm, 13C NMR; 77.00 ppm), DMSO-d 6 (1H NMR; 2.5 ppm, 13C NMR; 39.52 ppm). Signals are abbreviated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, and coupling constants are expressed in hertz. HRMS were performed with an Agilent LC/MSD TOF instrument. The reactions were monitored by thin-layer chromatography (TLC) using silica gel GF 254. Column chromatography was performed with 200–300 mesh silica gel. All yields refer to isolated products after purification. The melting points were determined with Tech X-5 melting-point apparatus and are uncorrected.
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Synthesis of 4; General Procedure
A mixture of 2-aminophenol 1 (109.1 mg, 1.0 mmol), diethyl but-2-ynedioate 2 (0.16 mL, 1.0 mmol), and EtOH/H2O (1:10 v/v; 3 mL) was placed into a dry reaction tube. The mixture was stirred at room temperature for 10 min until the completion of the reaction, which was monitored by TLC. Benzylamine 3 (0.11 mL, 1.0 mmol) was added to the reaction solution in one portion. The reaction was monitored by TLC, and was complete after 1 hour. The reaction was then quenched with brine and the mixture was extracted with EtOAc. The combined organic layer was dried over Na2SO4. After removal of Na2SO4 through filtration, the solution was concentrated under reduced pressure, and the mixture was purified by flash column chromatography over silica gel (mesh 200–300, gradient: petroleum ether/EtOAc (4:1 v/v)) to afford the desired maleimide derivatives 4a–z and 5a–m.
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1-Benzyl-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4a)
Yield: 264.7 mg (90%); yellow solid; mp 244.6–245.6 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.34 (s, 1 H, NH), 8.34 (s, 1 H, OH), 7.36–7.29 (m, 4 H, ArH), 7.28–7.25 (m, 2 H, ArH), 7.04–6.97 (m, 1 H, ArH), 6.93 (dd, J = 8.0, 1.3 Hz, 1 H, ArH), 6.86 (t, J = 7.5 Hz, 1 H, ArH), 5.56 (s, 1 H, CH), 4.62 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.9, 167.5, 147.9, 143.0, 137.0, 128.5, 128.3, 127.3, 127.2, 126.2, 125.1, 119.7, 119.4, 115.3, 87.7, 40.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H15N2O3 +: 295.1077; found: 295.1075.
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((2-Hydroxyphenyl)amino)-1-(4-methylbenzyl)-1H-pyrrole-2,5-dione (4b)
Yield: 265.0 mg (86%); yellow solid; mp 234.1–235.1 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.32 (s, 1 H, NH), 8.31 (s, 1 H, OH), 7.30 (dd, J = 7.9, 1.4 Hz, 1 H, ArH), 7.14 (s, 4 H, ArH), 7.03–6.98 (m, 1 H, ArH), 6.94 (d, J = 1.4 Hz, 1 H, ArH), 6.88–6.83 (m, 1 H, ArH), 5.54 (s, 1 H, CH), 4.56 (s, 2 H, CH2), 2.27 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 171.9, 167.4, 147.9, 142.9, 136.5, 134.0, 129.1, 127.3, 126.2, 125.1, 119.7, 119.3, 115.3, 87.7, 40.2, 20.6.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C18H17N2O3 +: 309.1234; found: 309.1226.
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1-(4-Chlorobenzyl)-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4c)
Yield: 252.6 mg (77%); yellow solid; mp 242.2–243.2 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.35 (s, 1 H, NH), 8.36 (s, 1 H, OH), 7.40 (dd, J = 8.3, 2.4 Hz, 2 H, ArH), 7.29 (t, J = 8.0 Hz, 3 H, ArH), 7.01 (t, J = 7.1 Hz, 1 H, ArH), 6.93 (d, J = 7.7 Hz, 1 H, ArH), 6.85 (t, J = 6.9 Hz, 1 H, ArH), 5.55 (d, J = 2.7 Hz, 1 H, CH), 4.61 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.8, 167.4, 148.0, 143.0, 136.0, 131.9, 129.2, 128.5, 126.2, 125.1, 119.7, 119.4, 115.4, 87.7, 39.8.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H14ClN2O3 +: 329.0687; found: 329.0678.
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1-(4-Bromobenzyl)-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4d)
Yield: 271.6 mg (73%); yellow solid; mp 242.4–243.4 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.35 (s, 1 H, NH), 8.36 (s, 1 H, OH), 7.55 (d, J = 2.0 Hz, 1 H, ArH), 7.54–7.52 (m, 1 H, ArH), 7.31 (dd, J = 7.9, 1.3 Hz, 1 H, ArH), 7.23 (d, J = 8.5 Hz, 2 H, ArH), 7.04–6.98 (m, 1 H, ArH), 6.94 (dd, J = 8.0, 1.4 Hz, 1 H, ArH), 6.87–6.83 (m, 1 H, ArH), 5.56 (s, 1 H, CH), 4.59 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.8, 167.4, 148.0, 143.0, 136.4, 131.4, 129.5, 126.2, 125.1, 120.4, 119.7, 119.4, 115.3, 87.7, 40.1.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H14BrN2O3 +: 373.0182; found: 373.0176.
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1-(2-Bromobenzyl)-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4e)
Yield: 293.9 mg (79%); yellow solid; mp 229.5–230.5 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.32 (s, 1 H, NH), 8.36 (s, 1 H, OH), 7.65 (d, J = 7.9 Hz, 1 H, ArH), 7.35 (q, J = 7.2, 2 H, ArH), 7.24 (t, J = 7.6 Hz, 1 H, ArH), 7.16 (d, J = 7.6 Hz, 1 H, ArH), 7.02 (t, J = 7.6 Hz, 1 H, ArH), 6.97–6.93 (m, 1 H, ArH), 6.88 (t, J = 7.6 Hz, 1 H, ArH), 5.62 (s, 1 H, CH), 4.65 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.1, 167.9, 148.5, 143.6, 135.9, 133.1, 129.8, 128.5, 126.7, 125.6, 122.0, 120.2, 119.9, 115.9, 88.4, 41.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H14BrN2O3 +: 373.0182; found: 373.0175.
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3-((2-Hydroxyphenyl)amino)-1-(naphthalen-2-ylmethyl)-1H-pyrrole-2,5-dione (4f)
Yield: 254.7 mg (85%); yellow solid; mp 263.5–264.5 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.34 (s, 1 H, NH), 8.34 (s, 1 H, OH), 7.90 (d, J = 8.0 Hz, 4 H, ArH), 7.77 (s, 1 H, ArH), 7.52–7.48 (m, 2 H, ArH), 7.43 (d, J = 8.2 Hz, 1 H, ArH), 7.33 (d, J = 7.7 Hz, 1 H, ArH), 7.01 (t, J = 7.6 Hz, 1 H, ArH), 6.94 (d, J = 7.6 Hz, 1 H, ArH), 6.87 (t, J = 7.6 Hz, 1 H, ArH), 5.60 (s, 1 H, CH), 4.79 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.9, 167.6, 148.2, 142.8, 133.1, 131.9, 130.2, 128.5, 127.8, 126.4, 126.2, 125.9, 125.3, 125.0, 124.9, 123.0, 119.4, 119.1, 115.3, 87.7, 38.5.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C21H17N2O3 +: 345.1234; found: 345.1231.
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3-((2-Hydroxyphenyl)amino)-1-phenethyl-1H-pyrrole-2,5-dione (4g)
Yield: 258.8 mg (84%); yellow solid; mp 236.1–237.1 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.39 (s, 1 H, NH), 8.17 (s, 1 H, OH), 7.30–7.26 (m, 3 H, ArH ), 7.23–7.11 (m, 3 H, ArH), 7.02–6.96 (m, 1 H, ArH), 6.92 (dd, J = 8.0, 1.5 Hz, 1 H), 6.86–6.82 (m, 1 H), 5.53 (s, 1 H), 3.65 (t, J = 7.3 Hz, 2 H), 2.85 (t, J = 7.2 Hz, 2 H, ArH).
13C NMR (100 MHz, DMSO-d 6): δ = 172.0, 167.4, 147.6, 142.2, 138.3, 128.6, 128.4, 126.4, 126.3, 124.8, 119.7, 118.8, 115.2, 87.8, 38.5, 33.8.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C18H17N2O3 +: 309.1234; found: 309.1228.
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3-((2-Hydroxyphenyl)amino)-1-(3-phenylpropyl)-1H-pyrrole-2,5-dione (4h)
Yield: 280.3 mg (87%); yellow solid; mp 227.2–228.2 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.36 (s, 1 H, NH), 8.21 (s, 1 H, OH), 7.32–7.24 (m, 3 H, ArH), 7.22 (t, J = 4.1 Hz, 2 H, ArH), 7.19–7.14 (m, 1 H, ArH), 7.02–6.96 (m, 1 H, ArH), 6.93 (dd, J = 8.0, 1.5 Hz, 1 H, ArH), 6.89–6.82 (m, 1 H, ArH), 5.54 (s, 1 H, CH), 3.44 (t, J = 7.0 Hz, 2 H, CH2), 2.62–2.53 (m, 2 H, CH2), 1.89–1.76 (m, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.3, 167.7, 147.7, 142.4, 141.2, 128.3, 128.2, 126.4, 125.8, 124.8, 119.7, 118.8, 115.2, 87.8, 36.8, 32.3, 29.8.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C19H19N2O3 +: 323.1390; found: 323.1383.
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3-((2-Hydroxyphenyl)amino)-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (4i)
Yield: 203.6 mg (69%); yellow solid; mp 233.4–234.4 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.29 (s, 1 H, NH), 8.52 (s, 1 H, OH), 8.49 (dd, J = 4.7, 1.3 Hz, 1 H, ArH), 7.67 (d, J = 7.9 Hz, 1 H, ArH), 7.37 (dd, J = 7.7, 4.8 Hz, 1 H, ArH), 7.30 (dd, J = 7.9, 1.1 Hz, 1 H, ArH), 7.02–6.98 (m, 1 H, ArH), 6.93 (dd, J = 8.0, 1.2 Hz, 1 H, ArH), 6.87–6.82 (m, 1 H, ArH), 5.55 (s, 1 H, CH), 4.66 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.8, 167.4, 148.8, 148.6, 148.1, 143.1, 135.2, 132.6, 126.2, 125.2, 123.7, 119.6, 119.4, 115.4, 87.7, 38.1.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C16H16N3O3 +: 296.1030; found: 296.1028.
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1-(Furan-2-ylmethyl)-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4j)
Yield: 213.1 mg (75%); yellow solid; mp 228.6–229.6 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.35 (s, 1 H, NH), 8.36 (s, 1 H, OH), 7.59 (s, 1 H, ArH), 7.30 (d, J = 8.0 Hz, 1 H, ArH), 7.02 (t, J = 7.2 Hz, 1 H, ArH), 6.93 (d, J = 8.1 Hz, 1 H, ArH), 6.86 (t, J = 7.6 Hz, 1 H, ArH), 6.40 (s, 1 H, CH), 6.33 (s, 1 H, CH), 5.53 (s, 1 H, CH), 4.61 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.3, 167.0, 149.7, 148.0, 143.0, 142.6, 126.1, 125.2, 119.7, 119.5, 115.4, 110.6, 107.8, 87.8, 33.7.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C15H13N2O4 +: 285.0870; found: 285.0865.
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1-(2-(1H-Indol-2-yl)ethyl)-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4l)
Yield: 295.1 mg (85%); yellow solid; mp 250.7–251.7 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.85 (s, 1 H, NH), 10.35 (s, 1 H, NH), 8.20 (s, 1 H, OH), 7.55 (d, J = 7.7 Hz, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH), 7.31 (dd, J = 17.0, 7.9 Hz, 2 H, ArH), 7.17 (s, 1 H, ArH), 7.07 (t, J = 7.5 Hz, 1 H, ArH), 7.00 (t, J = 6.8 Hz, 2 H, ArH), 6.93 (d, J = 7.9 Hz, 1 H, ArH), 6.86 (t, J = 7.5 Hz, 1 H, CH), 5.55 (s, 1 H, CH), 3.69 (t, J = 7.4 Hz, 2 H, CH2), 2.96 (t, J = 7.3 Hz, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.7, 168.1, 148.2, 142.9, 136.7, 127.5, 126.9, 125.3, 123.4, 121.5, 120.2, 119.3, 118.8, 118.5, 115.7, 111.9, 111.1, 88.3, 38.4, 24.6.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C20H18N3O3 +: 348.1343; found: 348.1333.
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3-((2-Hydroxyphenyl)amino)-1-methyl-1H-pyrrole-2,5-dione (4m)
Yield: 187.5 mg (86%); yellow solid; mp 213.9–214.9 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.39 (s, 1 H, NH), 8.22 (s, 1 H, OH), 7.29 (dd, J = 7.9, 1.3 Hz, 1 H, ArH), 7.02–6.96 (m, 1 H, ArH), 6.93 (dd, J = 8.0, 1.5 Hz, 1 H), 6.88–6.82 (m, 1 H, ArH), 5.56 (s, 1 H, CH), 2.89 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 172.4, 167.8, 147.6, 142.6, 126.3, 124.8, 119.7, 118.8, 115.2, 87.9, 23.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C11H11N2O3 +: 219.0764; found: 219.0757.
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1-Ethyl-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4n)
Yield: 201.9 mg (87%); yellow solid; mp 205.3–206.3 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.34 (s, 1 H, NH), 8.22 (s, 1 H, OH), 7.29 (d, J = 7.1 Hz, 1 H, ArH), 7.03–6.97 (m, 1 H, ArH), 6.93 (dd, J = 8.0, 1.2 Hz, 1 H, ArH), 6.88–6.83 (m, 1 H, ArH), 5.53 (s, 1 H, CH), 3.45 (q, J = 7.2 Hz, 2 H, CH2), 1.10 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 172.0, 167.5, 147.7, 142.6, 126.3, 124.8, 119.7, 118.9, 115.3, 87.8, 32.0, 13.8.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C12H13N2O3 +: 233.0921; found: 233.0918.
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3-((2-Hydroxyphenyl)amino)-1-propyl-1H-pyrrole-2,5-dione (4o)
Yield: 219.0 mg (89%); yellow solid; mp 191.5–192.5 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.34 (s, 1 H, NH), 8.22 (s, 1 H, OH), 7.29 (d, J = 6.8 Hz, 1 H, ArH), 7.02–6.97 (m, 1 H, ArH), 6.93 (dd, J = 8.0, 1.3 Hz, 1 H, ArH), 6.89–6.82 (m, 1 H, ArH), 5.54 (s, 1 H, CH), 3.38 (t, J = 7.1 Hz, 2 H, CH2), 1.59–1.48 (m, 2 H, CH2), 0.84 (t, J = 7.4 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 172.3, 167.7, 147.7, 142.4, 126.3, 124.8, 119.7, 118.9, 115.2, 87.7, 38.7, 21.5, 11.1.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C13H15N2O3 +: 247.1077; found: 247.1071.
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1-Butyl-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4p)
Yield: 234.1 mg (90%); yellow solid; mp 176.5–177.5 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.37 (s, 1 H, NH), 8.23 (s, 1 H, OH), 7.30 (d, J = 7.9 Hz, 1 H, ArH), 7.01 (m, 1 H, ArH), 5.65 (d, J = 9.0 Hz, 1 H, CH), 3.41 (t, J = 7.0 Hz, 2 H, CH2), 1.55–1.44 (m, 2 H, CH2), 1.29–1.20 (m, 2 H, CH2), 0.88 (t, J = 7.3 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 172.3, 167.7, 147.7, 142.4, 126.3, 124.8, 119.7, 118.9, 115.2, 87.7, 36.7, 30.2, 19.4, 13.5
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C14H17N2O3 +: 261.1234; found: 261.1227.
#
1-Hexadecyl-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4q)
Yield: 398.3 mg (93%); yellow solid; mp 148.6–149.6 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.35 (s, 1 H, NH), 8.19 (s, 1 H, OH), 7.29 (d, J = 8.0 Hz, 1 H, ArH), 6.99 (t, J = 7.6 Hz, 1 H, ArH), 6.93 (d, J = 8.0 Hz, 1 H, ArH), 6.85 (t, J = 7.6 Hz, 1 H, ArH), 5.53 (d, J = 1.6 Hz, 1 H, CH), 3.41 (t, J = 7.0 Hz, 2 H, CH2), 1.51 (t, J = 5.6 Hz, 2 H, CH2), 1.22 (s, 2 H, CH2), 0.84 (d, J = 6.6 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 172.7, 168.2, 148.2, 142.9, 126.9, 125.3, 120.2, 119.3, 115.7, 88.2, 37.5, 31.8, 29.5, 29.4, 29.3, 29.2, 29.0, 28.5, 26.6, 22.6, 14.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C26H41N2O3 +: 429.3112; found: 429.3100.
#
3-((2-Hydroxyphenyl)amino)-1-isobutyl-1H-pyrrole-2,5-dione (4r)
Yield: 231.5 mg (89%); yellow solid; mp 176.6–177.6 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.36 (s, 1 H, NH), 8.22 (s, 1 H, OH), 7.30 (dd, J = 8.0, 1.2 Hz, 1 H, ArH), 7.02–6.97 (m, 1 H, ArH), 6.93 (dd, J = 8.0, 1.3 Hz, 1 H, ArH), 6.88–6.83 (m, 1 H, ArH), 5.55 (s, 1 H, CH), 3.22 (d, J = 7.3 Hz, 2 H, CH2), 0.84 (d, J = 6.7 Hz, 6 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 172.4, 167.9, 147.7, 142.3, 126.3, 124.8, 119.7, 118.9, 115.2, 87.6, 44.4, 27.5, 19.9.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C14H17N2O3 +: 261.1234; found: 261.1230.
#
1-(2-(Diisopropylamino)ethyl)-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4s)
Yield: 288.1 mg (87%); yellow solid; mp 176.6–177.6 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.39 (s, 1 H, NH), 8.16 (s, 1 H, OH), 7.29 (dd, J = 7.9, 1.2 Hz, 1 H, ArH), 7.01–6.97 (m, 1 H, ArH), 6.93 (dd, J = 7.6, 1.2 Hz, 1 H, ArH), 6.88–6.83 (m, 1 H, ArH), 5.57 (s, 1 H, CH), 3.39 (t, J = 6.8 Hz, 2 H, CH2), 2.98–2.92 (m, 2 H, CH2), 0.92 (d, J = 6.5 Hz, 12 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 172.8, 168.2, 148.0, 142.7, 126.9, 125.2, 120.2, 119.0, 115.7, 88.3, 48.2, 42.8, 38.4, 21.0.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C18H26N3O3 +: 332.1969; found: 332.1936.
#
1-(Cyclopropylmethyl)-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4t)
Yield: 232.3 mg (90%); yellow solid; mp 184.0–185.0 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.37 (s, 1 H, NH), 8.28 (s, 1 H, OH), 7.30 (d, J = 8.0 Hz, 1 H, ArH), 7.04–6.97 (m, 1 H, ArH), 6.94 (d, J = 8.0 Hz, 1 H, ArH), 6.86 (t, J = 7.6 Hz, 1 H, ArH), 5.54 (d, J = 1.2 Hz, 1 H, CH), 3.29 (d, J = 7.2 Hz, 2 H, CH2), 1.11–0.96 (m, 1 H, CH), 0.49–0.42 (m, 2 H, CH2), 0.31–0.20 (m, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.2, 167.7, 147.8, 142.6, 126.3, 124.9, 119.7, 119.1, 115.3, 87.7, 41.4, 10.3, 3.5.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C14H15N2O3 +: 259.1077; found: 259.1073.
#
1-(Cyclohexylmethyl)-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4u)
Yield: 243.1 mg (81%); yellow solid; mp 204.8–205.8 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.34 (s, 1 H, NH), 8.22 (s, 1 H, OH), 7.30 (d, J = 7.4 Hz, 1 H, ArH), 7.05–6.78 (m, 3 H, ArH), 5.53 (s, 1 H, CH), 3.25 (d, J = 6.3 Hz, 2 H, CH2), 1.73–1.47 (m, 6 H, CH2), 1.15 (s, 3 H, CH2), 0.89 (d, J = 9.9 Hz, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.4, 167.8, 147.7, 142.3, 126.3, 124.9, 119.7, 118.9, 115.2, 87.6, 43.1, 36.6, 30.2, 25.8, 25.1.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H21N2O3 +: 301.1547; found: 301.1546.
#
3-((2-Hydroxyphenyl)amino)-1-isopropyl-1H-pyrrole-2,5-dione (4v)
Yield: 206.7 mg (84%); yellow solid; mp 179.8–180.8 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.33 (s, 1 H, NH), 8.16 (s, 1 H, OH), 7.28 (d, J = 7.6 Hz, 1 H, ArH), 7.02–6.96 (m, 1 H, ArH), 6.93 (dd, J = 8.0, 0.8 Hz, 1 H, ArH), 6.88–6.82 (m, 1 H, ArH), 5.51 (s, 1 H, CH), 4.24–4.18 (m, 1 H, CH), 1.32 (d, J = 6.9 Hz, 6 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 172.1, 167.4, 147.7, 142.2, 126.4, 124.8, 119.7, 118.8, 115.2, 87.7, 41.7, 20.0.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C13H15N2O3 +: 247.1077; found: 247.1070.
#
3-((2-Hydroxyphenyl)amino)-1-(1-phenylethyl)-1H-pyrrole-2,5-dione (4w)
Yield: 224.9 mg (73%); yellow solid; mp 182.5–183.5 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.36 (s, 1 H, NH), 8.26 (s, 1 H, OH), 7.40–7.32 (m, 4 H, ArH), 7.31–7.23 (m, 2 H, ArH), 7.03–6.96 (m, 1 H, ArH), 6.92 (dd, J = 8.0, 1.4 Hz, 1 H, ArH), 6.87–6.83 (m, 1 H, ArH), 5.54 (s, 1 H, CH), 5.27 (q, J = 7.3 Hz, 1 H, CH), 1.75 (d, J = 7.3 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 171.9, 167.4, 147.9, 142.5, 141.1, 128.4, 127.2, 126.4, 126.2, 125.0, 119.7, 119.2, 115.3, 87.6, 48.2, 17.8.
HRMS (ESI-TOF+): m/z calcd for C18H17N2O3 +: 309.1234; found: 309.1230.
#
1-Cyclopropyl-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4x)
Yield: 207.5 mg (85%); yellow solid; mp 196.1–197.1 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.34 (s, 1 H, NH), 8.13 (s, 1 H, OH), 7.27 (d, J = 8.0 Hz, 1 H, ArH), 7.02–6.96 (m, 1 H, ArH), 6.92 (dd, J = 6.4, 1.6 Hz, 1 H, ArH), 6.89–6.81 (m, 1 H, ArH), 5.50 (s, 1 H, CH), 2.49 (m, 1 H, CH), 0.86–0.76 (m, 4 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.5, 168.1, 147.6, 141.9, 126.4, 124.7, 119.7, 118.7, 115.2, 87.9, 19.9, 4.6.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C13H13N2O3 +: 245.0921; found: 245.0915.
#
1-Cyclopentyl-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4y)
Yield: 225.9 mg (85%); yellow solid; mp 201.0–202.0 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.36 (s, 1 H), 8.19 (s, 1 H), 7.28 (dd, J = 7.9, 1.2 Hz, 1 H), 7.01–6.96 (m, 1 H), 6.92 (dd, J = 8.0, 1.5 Hz, 1 H), 6.86–6.82 (m,1 H), 5.52 (s, 1 H), 4.38–4.29 (m, 1 H), 1.90–1.76 (m, 6 H), 1.55 (dd, J = 10.8, 4.4 Hz, 2 H).
13C{1H} NMR (100 MHz, DMSO-d 6): δ = 172.2, 167.4, 147.7, 142.3, 126.3, 124.8, 119.7, 118.8, 115.2, 87.7, 49.7, 29.2, 24.5.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C15H17N2O3 +: 273.1234; found: 273.1233.
#
1-Cyclohexyl-3-((2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (4z)
Yield: 231.8 mg (81%); yellow solid; mp 222.2–223.2 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.36 (s, 1 H, NH), 8.18 (s, 1 H, OH), 7.28 (dd, J = 8.0, 1.2 Hz, 1 H, ArH), 7.01–6.96 (m, 1 H, ArH), 6.92 (dd, J = 8.0, 1.4 Hz, 1 H, ArH), 6.88–6.76 (m, 1 H, ArH), 5.51 (s, 1 H, CH), 3.82–3.76 (m, 1 H, CH), 2.00–1.89 (m, 2 H, CH2), 1.77 (d, J = 13.0 Hz, 2 H, CH2), 1.62 (d, J = 12.1 Hz, 3 H, CH2), 1.33–1.22 (m, 2 H, CH2), 1.19–1.14 (m, 1 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.1, 167.4, 147.7, 142.2, 126.3, 124.8, 119.7, 118.9, 115.2, 87.6, 49.4, 29.7, 25.4, 24.9.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C16H19N2O3 +: 287.1390; found: 287.1389.
#
1-Benzyl-3-((2-hydroxy-5-methylphenyl)amino)-1H-pyrrole-2,5-dione (5a)
Yield: 280.4 mg (91%); yellow solid; mp 199.1–200.1 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.06 (s, 1 H, NH), 8.26 (s, 1 H, OH), 7.37–7.32 (m, 2 H, ArH), 7.30–7.24 (m, 3 H, ArH), 7.11 (s, 1 H, ArH), 6.84–6.77 (m, 2 H, ArH), 5.64 (s, 1 H, CH), 4.62 (s, 2 H, CH2), 2.24 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 171.9, 167.5, 145.5, 142.8, 137.0, 128.7, 128.5, 127.3, 127.2, 125.9, 125.3, 119.4, 115.2, 87.7, 40.4, 20.2.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C18H17N2O3 +: 309.1234; found: 309.1225.
#
1-Benzyl-3-((2-hydroxy-4-methylphenyl)amino)-1H-pyrrole-2,5-dione (5b)
Yield: 280.4 mg (91%); yellow solid; mp 220.6–221.6 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.21 (s, 1 H, NH), 8.34 (s, 1 H, OH), 7.35 (dd, J = 11.2, 4.3 Hz, 2 H, ArH), 7.30–7.24 (m, 3 H, ArH), 7.18 (d, J = 8.0 Hz, 1 H, ArH), 6.75 (d, J = 1.1 Hz, 1 H, ArH), 6.67 (d, J = 8.1 Hz, 1 H, ArH), 5.45 (s, 1 H, CH), 4.61 (s, 2 H, CH2), 2.23 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 171.8, 167.4, 148.0, 143.4, 137.1, 134.8, 128.5, 127.3, 127.2, 123.6, 120.2, 119.6, 116.0, 87.0, 40.4, 20.7.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C18H17N2O3 +: 309.1234; found: 309.1224.
#
1-Benzyl-3-((5-(tert-butyl)-2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (5c)
Yield: 297.6 mg, 85%; yellow solid; mp 228.1–229.1 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.00 (s, 1 H, NH), 8.46 (s, 1 H, OH), 7.34 (t, J = 7.2 Hz, 2 H, ArH), 7.27 (t, J = 8.0 Hz, 3 H, ArH), 7.18 (d, J = 2.3 Hz, 1 H, ArH), 7.05 (dd, J = 8.4, 2.4 Hz, 1 H, ArH), 6.86 (d, J = 8.4 Hz, 1 H, ArH), 5.28 (s, 1 H, CH), 4.62 (s, 2 H, CH2), 1.25 (s, 9 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 171.8, 167.3, 146.2, 143.9, 142.0, 137.1, 128.5, 127.3, 127.2, 125.4, 122.3, 117.2, 115.3, 87.0, 40.4, 33.9, 31.2.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C21H23N2O3 +: 351.1703; found: 351.1694.
#
1-Benzyl-3-((2-hydroxy-3,5-dimethylphenyl)amino)-1H-pyrrole-2,5-dione (5d)
Yield: 235.2 mg (73%); yellow solid; mp 197.6–198.6 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.89 (s, 1 H, NH), 8.54 (s, 1 H, OH), 7.37–7.31 (m, 2 H, ArH), 7.27 (t, J = 7.0 Hz, 3 H, ArH), 6.94 (s, 1 H, ArH), 6.74 (s, 1 H, ArH), 5.46 (s, 1 H, CH), 4.62 (s, 2 H, CH2), 2.21 (s, 3 H, CH3), 2.17 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 171.9, 167.4, 143.9, 143.7, 137.1, 128.9, 128.5, 127.5, 127.3, 127.2, 126.7, 125.7, 118.1, 87.3, 40.3, 20.2, 16.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C19H19N2O3 +: 323.1390; found: 323.1380.
#
1-Benzyl-3-((2-hydroxy-5-methoxyphenyl)amino)-1H-pyrrole-2,5-dione (5e)
Yield: 278.7 mg (86%); yellow solid; mp 231.9–232.9 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 9.78 (s, 1 H, NH), 8.31 (s, 1 H, OH), 7.34 (t, J = 7.2 Hz, 3 H, ArH), 7.27 (t, J = 7.0 Hz, 3 H, ArH), 6.85 (d, J = 8.8 Hz, 1 H, ArH), 6.80 (d, J = 2.4 Hz, 1 H, ArH), 6.60 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 5.54 (s, 1 H, CH), 4.62 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d 6): δ = 171.8, 167.4, 152.5, 142.8, 141.8, 137.0, 128.5, 127.3, 127.2, 126.7, 116.0, 110.1, 105.4, 88.1, 55.5, 40.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C18H17N2O4 +: 325.1183; found: 325.1177.
#
Methyl 3-((1-Benzyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)-4-hydroxybenzoate (5f)
Yield: 285.2 mg (81%); yellow solid; mp 224.9–225.9 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.20 (s, 1 H, NH), 8.60 (s, 1 H, OH), 7.77 (d, J = 2.0 Hz, 1 H, ArH), 7.68 (dd, J = 8.5, 2.0 Hz, 1 H, ArH), 7.37–7.31 (m, 2 H, ArH), 7.27 (t, J = 6.6 Hz, 3 H, ArH), 7.03 (d, J = 8.5 Hz, 1 H, ArH), 5.24 (s, 1 H, CH), 4.62 (s, 2 H, CH2), 3.81 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 171.5, 167.1, 165.6, 153.5, 144.2, 137.0, 128.5, 127.5, 127.3, 127.2, 126.2, 121.9, 120.8, 115.7, 88.1, 51.9, 40.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C19H17N2O5 +: 353.1132; found: 353.1125.
#
1-Benzyl-3-((5-chloro-2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (5g)
Yield: 255.9 mg (78%); yellow solid; mp 215.9–216.9 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.58 (s, 1 H, NH), 8.43 (s, 1 H, OH), 7.38–7.31 (m, 2 H, ArH), 7.27 (dd, J = 8.6, 5.8 Hz, 3 H, ArH), 7.06 (dd, J = 8.6, 2.4 Hz, 1 H, ArH), 6.93 (d, J = 8.6 Hz, 1 H, ArH), 5.56 (s, 1 H, CH), 4.61 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.7, 167.3, 149.2, 143.1, 137.0, 128.5, 127.3, 127.2, 125.5, 121.0, 119.3, 115.2, 88.4, 40.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H14ClN2O3 +: 329.0687; found: 329.0680.
#
1-Benzyl-3-((4-chloro-2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (5h)
Yield: 262.5 mg (80%); yellow solid; mp 225.3–226.3 °C.
1HNMR (400 MHz, DMSO-d 6): δ = 10.84 (s, 1 H, NH), 8.37 (s, 1 H, OH), 7.37–7.21 (m, 6 H, ArH), 6.98–6.83 (m, 2 H, ArH), 5.53 (s, 1 H, CH), 4.61 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.2, 167.8, 147.9, 143.5, 137.5, 129.0, 127.7, 125.3, 123.4, 119.8, 117.2, 89.6, 41.0.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H14ClN2O3 +: 329.0687; found: 329.0680.
#
1-Benzyl-3-((5-bromo-2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (5i)
Yield: 290.2 mg (78%); yellow solid; mp 231.5–232.5 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.86 (s, 1 H, NH), 8.36 (s, 1 H, OH), 7.35 (dd, J = 11.2, 4.4 Hz, 3 H, ArH), 7.30–7.23 (m, 6 H, ArH), 7.08 (d, J = 2.2 Hz, 1 H, ArH), 7.01 (dd, J = 8.5, 2.2 Hz, 1 H, ArH), 5.55 (s, 1 H, CH), 4.61 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.8, 167.3, 149.3, 142.9, 137.0, 128.5, 128.3, 127.3, 127.2, 125.9, 122.2, 121.3, 118.0, 116.4, 88.6, 40.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H14BrN2O3 +: 373.0182; found: 373.0171.
#
1-Benzyl-3-((4-bromo-2-hydroxyphenyl)amino)-1H-pyrrole-2,5-dione (5j)
Yield: 293.9 mg (79%); yellow solid; mp 239.9–240.9 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.85 (s, 1 H, NH), 8.37 (s, 1 H, OH), 7.39–7.21 (m, 6 H, ArH), 6.95 (d, J = 2.3 Hz, 1 H, ArH), 6.89 (dd, J = 8.5, 2.3 Hz, 1 H, ArH), 5.53 (s, 1 H, CH), 4.61 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.7, 167.3, 149.2, 143.1, 137.0, 128.5, 127.3, 127.2, 125.5, 121.0, 119.3, 115.2, 88.4, 40.4.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C17H14BrN2O3 +: 373.0182; found: 373.0172.
#
3-((1-Benzyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)-4-hydroxybenzonitrile (5k)
Yield: 232.9 mg (73%); yellow solid; mp 235.1–236.1 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.59 (s, 1 H, NH), 8.39 (s, 1 H, OH), 7.70 (s, 1 H, ArH), 7.48 (d, J = 8.0 Hz, 1 H, ArH), 7.42–7.10 (m, 5 H, ArH), 7.05 (d, J = 8.0 Hz, 1 H, ArH), 5.80 (s, 1 H, CH), 4.62 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.7, 167.4, 152.7, 142.6, 136.9, 130.1, 128.5, 127.3, 127.2, 122.7, 119.0, 116.1, 114.1, 101.6, 89.9, 40.5.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C18H13N3O3 +: 320.1030; found: 320.0125.
#
1-Benzyl-3-((3-hydroxynaphthalen-2-yl)amino)-1H-pyrrole-2,5-dione (5l)
Yield: 244.3 mg (77%); yellow solid; mp 271.7–272.7 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.03 (s, 1 H, NH), 8.32 (s, 1 H, OH), 7.93 (d, J = 7.7 Hz, 1 H, ArH), 7.82 (s, 1 H, ArH), 7.68 (d, J = 7.7 Hz, 1 H, ArH), 7.37–7.32 (m, 4 H, ArH), 7.31–7.23 (m, 5 H, ArH), 6.23 (s, 1 H, CH), 4.66 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 172.6, 168.2, 146.7, 141.6, 137.4, 131.1, 129.1, 128.8, 128.4, 127.9, 127.8, 127.7, 126.2, 125.7, 124.1, 114.4, 109.3, 90.6, 41.1.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C21H17N2O3 +: 345.1234; found: 345.1228.
#
3-((2-Hydroxyphenyl)amino)-1-(naphthalen-2-ylmethyl)-1H-pyrrole-2,5-dione (5m)
Yield: 268.0 mg (68%); yellow solid; mp 281.5–282.5 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 11.03 (s, 1 H, NH), 8.34 (s, 1 H, OH), 7.96–7.88 (m, 4 H, ArH), 7.82 (d, J = 12.4 Hz, 2 H, ArH), 7.68 (d, J = 7.7 Hz, 1 H, ArH), 7.54–7.48 (m, 3 H, ArH), 7.45 (d, J = 8.5 Hz, 1 H, ArH), 7.33 (m, 2 H, ArH), 7.26 (s, 1 H, ArH), 6.27 (s, 1 H, CH), 4.83 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d 6): δ = 171.9, 167.6, 147.9, 142.9, 134.6, 132.8, 132.2, 128.2, 127.6, 127.5, 126.3, 126.3, 126.0, 125.6, 125.5, 125.1, 119.7, 119.2, 115.4, 87.9, 40.7.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C25H19N2O3 +: 395.1390; found: 395.1353.
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Ethyl (E)-3-(2-((1-Benzyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)((E)-3-ethoxy-3-oxoprop-1-en-1-yl)amino)phenoxy)acrylate (4aa)
Yield: 397.04 mg (81%); yellow solid; mp 204.1–205.1 °C.
1H NMR (400 MHz, CDCl3): δ = 8.93 (d, J = 13.6 Hz, 1 H), 7.54 (d, J = 12.2 Hz, 1 H), 7.48–7.43 (m, 1 H), 7.29–7.15 (m, 8 H), 5.53 (d, J = 12.2 Hz, 1 H), 4.93 (s, 1 H), 4.69 (d, J = 13.6 Hz, 1 H), 4.58 (s, 2 H), 4.11–4.05 (m, 4 H), 1.20–1.14 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 167.9, 165.8, 165.3, 164.4, 155.7, 150.1, 144.2, 142.4, 135.2, 130.6, 128.4, 127.7, 127.5, 127.0, 126.8, 125.4, 118.1, 103.8, 100.8, 99.7, 59.3, 59.2, 40.4, 13.3, 13.2.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C27H27N2O7 +: 491.1813; found: 491.1817.
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Ethyl (E)-2-(2-oxo-2H-benzo[b][1,4]oxazin-3(4H)-ylidene)acetate (6)
Yield: 200.4 mg (86%); yellow solid; mp 100.2–100.9 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.70 (s, 1 H, NH), 7.51 (dd, J = 8.0, 1.3 Hz, 1 H, ArH), 7.18 (dd, J = 8.7, 4.7 Hz, 1 H, ArH), 7.14 (dd, J = 7.8, 1.1 Hz, 1 H, ArH), 7.05–7.00 (m, 1 H, ArH), 5.59 (s, 1 H, CH), 4.17 (q, J = 7.1 Hz, 2 H, CH2), 1.25 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 168.2, 155.9, 139.8, 138.7, 125.1, 124.6, 122.4, 116.2, 116.0, 88.5, 59.6, 14.2.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C12H12NO4 +: 234.0761; found: 234.0756.
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Ethyl (Z)-4-(Benzylamino)-3-((2-hydroxyphenyl)amino)-4-oxobut-2-enoate (7)
Yield: 306.1 mg (90%); yellow solid; mp 167.2–168.2 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 10.03 (s, 1 H, NH), 9.94 (s, 1 H, OH), 9.36 (t, J = 6.0 Hz, 1 H, NH), 7.34 (dd, J = 9.1, 5.6 Hz, 2 H, ArH), 7.28 (t, J = 6.0 Hz, 3 H, ArH), 6.87–6.77 (m, 2 H, ArH), 6.65 (d, J = 7.8 Hz, 1 H, ArH), 6.52–6.45 (m, 1 H, ArH), 4.88 (s, 1 H, CH), 4.34 (d, J = 6.0 Hz, 2 H, CH2), 4.12 (q, J = 7.1 Hz, 2 H, CH2), 1.21 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d 6): δ = 168.9, 163.9, 152.2, 146.9, 138.4, 128.3, 127.6, 127.2, 127.0, 123.3, 118.9, 118.1, 114.9, 88.2, 59.1, 42.4, 14.3.
HRMS (ESI-TOF+): m/z [M + H]+ calcd for C19H21N2O4 +: 341.1496; found: 341.1496.
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Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We thank Prof. Xiao-Nian Li, Kunming Institute of Botany, Chinese Academy of Sciences, for X-ray crystallographic analysis.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0042-1751406.
- Supporting Information
- CIF File
-
References
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- 3b Imoto H, Nohmi K, Kizaki K, Watase S, Matsukawa K, Yamamoto S, Mitsuishi M, Naka K. RSC Adv. 2015; 5: 94344
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- 6a Huang C.-H, Chattopadhyay B, Gevorgyan V. J. Am. Chem. Soc. 2011; 133: 12406
- 6b Jiang G.-B, Fang S.-J, Hu W.-G, Li J.-X, Zhu C.-L, Wu W.-Q, Jiang H.-F. Adv. Synth. Catal. 2018; 360: 2297
- 7 He J.-H, Dong J.-Y, Su L.-B, Wu S.-F, Liu L.-X, Yin S.-F, Zhou Y.-B. Org. Lett. 2020; 22: 2522
- 8a Li J.-P, Wang S, Xu G.-R, Cui X, Zi B.-Q, Liu T, Huang C. Asian J. Org. Chem. 2022; 11: e202100797
- 8b Li W.-Q, Wu Q, Xu G.-R, Sun Y.-J, Huang C, Liu T. Asian J. Org. Chem. 2021; 10: 3370
- 8c Wu Q, Xu G.-R, Li W.-Q, Wan J, Liu T, Huang C. Org. Lett. 2022; 24: 3950
- 8d Wang L.-F, Li S, Xiao X.-Q, Xu W.-M, Zhang P.-F, Ma Y.-M. Adv. Synth. Catal. 2022; 364: 355
- 8e Ding Y.-X, Zhang R.-Q, Ma R.-C, Ma Y.-M. Adv. Synth. Catal. 2022; 364: 855
- 9 CCDC 2210943 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
Corresponding Authors
Publication History
Received: 25 November 2022
Accepted after revision: 14 December 2022
Article published online:
12 January 2023
© 2023. Thieme. All rights reserved
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1a Xie Y.-J, Husband J.-T, Torrent-Sucarrat M, Yang H, Liu W.-S, O’Reilly R.-K. Chem. Commun. 2018; 54: 3339
- 1b Li B, Mao Q, Zhou J, Liu F, Ye N. Org. Biomol. Chem. 2019; 17: 2242
- 1c Liu S.-L, Shi Y.-J, Xue C, Zhang L, Zhou L, Song M.-P. Eur. J. Org. Chem. 2021; 5862
- 1d Tan M, Wang X.-Y, Xie T, Zhang Z, Shi Y, Li Y.-C, Chen Y.-M. Macromolecules 2022; 55: 686
- 2a Gunosewoyo H, Midzak A, Gaisina I.-N, Sabath E.-V, Fedolak A, Hanania T, Brunner D, Papadopoulos V, Kozikowski A.-P. J. Med. Chem. 2013; 56: 5115
- 2b Husband J.-T, Xie Y.-J, Wilks T.-R, Male L, Torrent-Sucarrat M, Stavros V.-G, O’Reilly R.-K. Chem. Sci. 2021; 12: 10550
- 2c Xu Y.-L, Zhou X.-Y, Chen L.-Y, Ma Y.-F, Wu G. Org. Chem. Front. 2022; 9: 2471
- 2d He Y, Li W, Zhou H, Zeng G, Chen Z, Ge J, Lv N, Chen J. Adv. Synth. Catal. 2022; 364: 3730
- 3a Chepyshev S.-V, Chepysheva Y.-N, Ryabitskii A.-B, Prosyanik A.-V. Chem. Heterocycl. Compd. 2008; 44: 523
- 3b Imoto H, Nohmi K, Kizaki K, Watase S, Matsukawa K, Yamamoto S, Mitsuishi M, Naka K. RSC Adv. 2015; 5: 94344
- 3c Zhu Q.-H, Ye ZW, Yang W.-J, Cai X.-T, Tang B.-Z. J. Org. Chem. 2017; 82: 1096
- 4a Awuah E, Capretta A. J. Org. Chem. 2011; 76: 3122
- 4b Mabire A.-B, Robin M.-P, Quan W.-D, Willcock H, Stavros V.-G, O’Reilly R.-K. Chem. Commun. 2015; 51: 9733
- 5a An Y.-L, Zhang H.-H, Yang Z.-H, Lin L, Zhao S.-Y. Eur. J. Org. Chem. 2016; 5405
- 5b Zhou X.-Y, Shi S.-S, Chen L.-Y, Wu G, Ma Y.-F. Adv. Synth. Catal. 2022; 364: 3522
- 5c Guo Y, Yao L.-L, Luo L, Wang H.-X, Yang Z, Wang Z, Ai S.-L, Zhang Y.-X, Zou Q.-C, Zhang H.-L. Org. Chem. Front. 2021; 8: 239
- 6a Huang C.-H, Chattopadhyay B, Gevorgyan V. J. Am. Chem. Soc. 2011; 133: 12406
- 6b Jiang G.-B, Fang S.-J, Hu W.-G, Li J.-X, Zhu C.-L, Wu W.-Q, Jiang H.-F. Adv. Synth. Catal. 2018; 360: 2297
- 7 He J.-H, Dong J.-Y, Su L.-B, Wu S.-F, Liu L.-X, Yin S.-F, Zhou Y.-B. Org. Lett. 2020; 22: 2522
- 8a Li J.-P, Wang S, Xu G.-R, Cui X, Zi B.-Q, Liu T, Huang C. Asian J. Org. Chem. 2022; 11: e202100797
- 8b Li W.-Q, Wu Q, Xu G.-R, Sun Y.-J, Huang C, Liu T. Asian J. Org. Chem. 2021; 10: 3370
- 8c Wu Q, Xu G.-R, Li W.-Q, Wan J, Liu T, Huang C. Org. Lett. 2022; 24: 3950
- 8d Wang L.-F, Li S, Xiao X.-Q, Xu W.-M, Zhang P.-F, Ma Y.-M. Adv. Synth. Catal. 2022; 364: 355
- 8e Ding Y.-X, Zhang R.-Q, Ma R.-C, Ma Y.-M. Adv. Synth. Catal. 2022; 364: 855
- 9 CCDC 2210943 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
