Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 8315−8321
Cu(II)-Catalyzed Ortho-C−H Nitration of Aryl Ureas By C−H Functionalization Chun-Meng Wang, Kai-Xiang Tang, Tian-Hong Gao, Lin Chen, and Li-Ping Sun* Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China
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S Supporting Information *
ABSTRACT: A novel protocol for the aromatic ortho C−H nitration of aryl ureas with Fe(NO3)3·9H2O is developed. The reaction utilizes CuCl2·2H2O as catalyst and p-TSA as additive, showing good functional group tolerance and furnishing the desired products in moderate to excellent yields.
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INTRODUCTION Urea derivatives are widely used in many roles, including those used as biologically active compounds, as pharmaceuticals, as agricultural pesticides, and as antioxidants in gasoline1 (Figure 1). Additionally, urea derivatives are also important units in
and practical synthetic approach. However, the poor selectivity and imperfect functional group tolerance restrict their application.7 To overcome these drawbacks, several approaches have been explored including the nitration of aryl halides, pseudohalides, and organometallic compounds.8 However, they still suffer from the requirement of prefunctionalized substrate precursors. The direct transformations of the C−H bond to the C−NO2 bond have drawn attention because they could improve the atom economy and simplify the operation. In recent decades, transition-metal-catalyzed chelation assisted C−H functionalization has been widely explored and extensively employed in organic synthesis. In 2010, Xu and Liu9a reported the first example of a palladium-catalyzed direct ortho-nitration of aryl C−H bonds using azaarenes as the directing functional groups. Since then, the chelation-directed strategy was explored using transition metals such as palladium,9 copper,10 ruthenium,11 and so on12 with various nitro sources. Despite the advances, most of these reactions suffered from the use of N-heterocycles as the directing groups, which are difficult to remove, thus having some limitation in substrate scopes. Besides, some of them need harsh reaction conditions which hamper the further application. Therefore, an easily available nitro source, convenient reaction conditions, and good regioselectivity are still the long-standing goal for the nitration. Herein, we report the orthoC−H nitration of ureas using ureas as the directing groups, which proceeds under convenient conditions in the presence of CuCl2·2H2O as catalyst with Fe(NO3)3·9H2O utilized as nitro source.
Figure 1. Bioactive compounds containing urea scaffolds examples.
organic synthesis. A quite important application of them is served as excellent ortho-directing functional groups in the activation of C−H bonds by transition metal catalysts. With their utilization, methods have been established for the implementation of direct ortho-C−C bond formation such as arylation,2 carbonylation,3 alkenylation,4 and other reactions.5 However, in comparison with the well-established chelationassisted transition metal catalyzed C−C bond formation, the direct C−N bond formation by using ureas as directing groups is unknown. Aromatic nitro compounds are widely used as raw materials in many disciplines of the chemical industry and also are essential constituents in some therapeutic and pharmaceutically relevant molecules.6 Until now, numerous useful methods for their preparation have been developed. In these methods, the electrophilic nitration of arenes have long been the classic © 2018 American Chemical Society
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RESULTS AND DISCUSSION In our initial investigation, the reaction was performed by using N,N-dimethyl-N′-(4-methylphenyl)urea (1a) as a model substrate with CuCl2·2H2O (0.4 equiv), Fe(NO3)3·9H2O (0.35 equiv) and p-TSA (1 equiv) in 1,2-dichloroethane (DCE) at 80 °C under air. To our delight, the reaction Received: April 22, 2018 Published: July 3, 2018 8315
DOI: 10.1021/acs.joc.8b01016 J. Org. Chem. 2018, 83, 8315−8321
Article
The Journal of Organic Chemistry Table 1. Optimization Studies for the Cu-Catalyzed Nitration of Ureasa
entry
catalyst
nitro source
additive
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuCl2·2H2O CuBr2 Cu(OTf)2 Cu(OAc)2·H2O Cu(NO3)2·3H2O
Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Cu(NO3)2·3H2O AgNO2 Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O Fe(NO3)3·9H2O
p-TSA p-TSA p-TSA HOAc TFA TfOH PivOH p-TSA p-TSA p-TSA p-TSA p-TSA p-TSA p-TSA p-TSA p-TSA p-TSA p-TSA p-TSA
DCE DCE DCE DCE DCE DCE DCE DCE DCE toluene CH3CN THF toluene toluene toluene toluene toluene toluene toluene
77 78c 52d 60 80 80 68 57 N.D.e 89 54 60 84 90 88 78 N.D.e 84f 74g
CuCl2·2H2O CuCl2·2H2O
Reaction conditions: N,N-dimethyl-N′-(4-methylphenyl)urea (1a) (0.11 mmol, 1 equiv), Fe(NO3)3·9H2O (0.0385 mmol, 0.35 equiv), Cu salt (0.044 mmol, 0.4 equiv), additive (0.11 mmol, 1 equiv), and solvent (3 mL), reflux. bIsolated yield. cReaction was carried out under N2 using a N2 balloon assembly. dReaction was carried out under O2 using a O2 balloon assembly. eN.D. = not detected. fCuCl2·2H2O (0.022 mmol, 0.2 equiv). g p-TSA(0.055 mmol, 0.5 equiv) a
occurred at the ortho-position of the N-aryl ring and gave product 2a in 77% yield (Table 1, entry 1). Sequentially, we conducted the reaction under O 2 atmosphere and N 2 atmosphere, respectively, to explore whether the atmosphere was able to improve the yield of the product. However, the yields were not increased (entries 2−3). Then additives were taken into consideration. Some other acids such as HOAc, TFA, TfOH, and PivOH were used, and the best result of them was at the same level compared with p-TSA (entries 4−7). Next, among the nitro sources examined, Fe(NO3)3·9H2O gave the best result, whereas Cu(NO3)2·3H2O and AgNO2 afforded the target product in less than 60% yield (entries 8− 9). For the solvents, toluene was found to be the optimum choice, which gave the highest yield (89%) at reflux temperature (entries 10−12). Afterward, a screening of copper sources showed that no obviously increased yield was exhibited (entries 13−16). Control experiment confirmed that no reaction was observed without the Cu source (entry 17). Additionally, lowering the amount of the Cu source (20 mol %) did not lead to the formation of 2a in a drastically decreased yield (entry 18). However, the yield decreased to 74% when the amount of p-TSA was controlled to 0.5 equiv (entry 19). Finally, the standard reaction conditions for the synthesis was identified as follows: 0.2 equiv CuCl2·2H2O as the catalyst, 0.35 equiv Fe(NO3)3·9H2O as the nitro source, 1 equiv p-TSA as the additive, and toluene as the solvent under an air atmosphere at 110 °C. With the optimized reaction conditions established, the scope and functional groups compatibility of this protocol was explored (Scheme 1). For the N,N-dimethyl-N′-arylureas, the urea containing unsubstituted phenyl ring reacted smoothly to form the product 2f in a yield of 60%. A substrate bearing an
electron-donating functional group (1g) produced the product in excellent yield (2g), whereas 1j, 1k having ortho-methoxy and meta-methoxy substituents were less reactive giving the products in less than 60% yield. Slightly electron-withdrawing groups furnished the desired products in moderate yields (2b− 2e), which could offer platforms for further functionalization as they contain halogens. The strong electron-withdrawing groups, − CF3 and − COOCH3, drastically decreased the yields and the expected product 2h and 2i were obtained in 35% and 38% yields, respectively. Disubstituted substrates bearing methoxy and bromo groups at the 3- and 4-positions provided the products (2l and 2m) in good yields (55 and 59%). Besides, a disubstituted substrate bearing fluoro and chloro groups at the 4- and 3-positions also provided the orthonitrated product (2n) in 33% yield. However, substrate that the 2- and 4-positions were occupied by chloro groups offered the product in trace yield. Interestingly, when methoxy substituted the 3- and 5-positions, the substrate (1o) did not give the corresponding product (2o). Next, we investigated the application of ureas equipped with different alkyl substituents on the nitrogen atom. Changing the dimethylamino moiety to cyclic diamines had no influence on the reaction, and thereby piperidine and morpholine urea derivatives reacted excellently to provide 2s and 2t in 90% and 87% yields. At the same time, ureas which were constituted by primary amines were also studied. We found that N-ethyl urea could be transformed smoothly under the catalytic conditions to 2q. Nevertheless, N-methoxy urea was restricted to provide the product 2r. Given the operational simplicity of this method, we performed a gram scale reaction (Scheme 2a), and the nitration product was obtained in 60% yield. To demonstrate 8316
DOI: 10.1021/acs.joc.8b01016 J. Org. Chem. 2018, 83, 8315−8321
Article
The Journal of Organic Chemistry Scheme 1. Substrate Scope of the Nitrationa,b,c
converted to other functional groups (e.g., Cl, Br, I, CN···) via Sandmeyer reactions. To gain insights into the reaction pathway, additional experiments were performed. Radical scavenger TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added under the standard reactions (Scheme 3a) to figure out whether a radical intermediate was involved in the reaction. Although the yield was decreased, the reaction was not completely suppressed, suggesting that a radical pathway might not be involved. Then we performed an intermolecular competition experiment between an electron-rich substrate (1g) and electron-deficient substrate (1i) under the optimized conditions. The products 2g and 2i were isolated in equal yields, which indicated that C−H activation was not involved in the rate-limiting step of this transformation. Next, when phenyl dimethylcarbamate (4) was used as a substrate, the nitration product 5 was not obtained, indicating that the NH group of ureas is indispensable for the regioselective nitration. Although details about the mechanism remained to be ascertained, on the basis of these observations and earlier precedents,10d a plausible mechanism for this reaction was depicted in Scheme 4. The substrate 1 may first bind with CuCl2·2H2O to give an intermediate 6 that may undergo reaction with Fe(NO3)3·9H2O to afford the intermediate 7. The subsequent intramolecular ortho-nitration via an aromatic electrophilic substitution can give the intermediate 8, which can afford the target product 2 and the hydrated CuCl2 to complete the catalytic cycle.
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CONCLUSIONS In summary, we have developed a novel and efficient coppercatalyzed, highly regioselective, direct C−H nitration of ureas with iron nitrate as a nitro source by utilizing ureas as directing groups. The present method tolerates a variety of functional groups and allows the synthesis of diverse nitrated urea derivatives in moderate to excellent yields. This therefore represents an important extension of the chemistry of urea compounds.
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Reaction conditions: ureas 1 (0.25 mmol, 1 equiv), Fe(NO3)3·9H2O (0.0875 mmol, 0.35 equiv), CuCl2·2H2O (0.05 mmol, 0.2 equiv), pTSA (0.25 mmol, 1 equiv), toluene (3 mL), reflux. bIsolated yield. c N.D. = not detected. a
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all chemical reagents were commercially purchased and used without further purification. Analytical TLC was carried out by using pre-254 coated plates and visualized with UV light. Melting points (uncorrected) were determined on a RY-1 MP apparatus. 1H and 13C NMR spectra were recorded on a Bruker AV-300 spectrometer at 300 and 75 MHz, respectively. Chemical shifts are reported in δ (ppm), relative to the internal standard of TMS. The signals observed are described as s (singlet), d (doublet), t (triplet), q (quartet), and m (multiple). Coupling constants are reported as J values in units of Hz. Mass spectrometry was obtained by using a Q-TOF high-resolution mass spectrometer. Flash column chromatography was performed over silica gel 200−300 m. General Procedure for the Substrates 1a−1t. All the starting substrates (1a−1t) for nitration were prepared according to literature reported methods.4c,5a Method a: aniline derivatives (500 mg, 4.67 mmol) and triethylamine (1.3 mL, 9.34 mmol) were dissolved in a two neck round-bottom flask followed by dropwise addition of chlorofomic acid dimethyl amide (1.8 mL, 20 mmol) using a syringe. The reaction mixture was stirred at room temperature. After completion, the reaction was diluted with DCM (30 mL), washed by 2 N HCl (15 × 3 mL), brine (15 × 3 mL). After being dried over Na2SO4, the organic solvent was removed by evaporation. Then the crude mixture was
Scheme 2. Gram Scale Reaction and Nitroarenes Transformation
the utility of this method, we carried out a few transformations using the nitration products as starting materials. Hydrogenation of 2a under Pd/C and H2 condition provided aniline in excellent yield (Scheme 2b), which could be conveniently 8317
DOI: 10.1021/acs.joc.8b01016 J. Org. Chem. 2018, 83, 8315−8321
Article
The Journal of Organic Chemistry Scheme 3. Control Experiments
Scheme 4. Proposed Catalytic Cycle
purified by flash column chromatography (DCM/EA 50:1) to give 1a−1q. Method b: a solution of triphosgene (0.59 g, 2 mmol) in dry DCM (10 mL) was prepared under an N2 atmosphere in a two neck dried round-bottom flask and cooled to 0 °C. A solution of aryl amine (5.0 mmol) and triethylamine (1.38 mL, 10 mmol) in DCM (10 mL), which was prepared in a dried round-bottom flask, was added slowly via cannula. After 15 min, the ice bath was removed, and the reaction mixture was allowed to stir at room temperature until the TLC analysis indicated conversion of the amine. In a separate dried flask, dry triethylamine (1.52 mL, 11 mmol) was added under an N2 atmosphere to a solution of corresponding amine (5.5 mmol) in dry DMF (10 mL) at room temperature. The resulting white suspension was cooled to 0 °C, and the solution containing the isocyanate was added via cannula. The ice bath was removed, and the reaction mixture was stirred for 10−12 h. The solvent was removed under vacuum and the residue suspended in DCM and filtered to remove the nonsoluble triethylammoniumchloride salt. Then 1q−1t were obtained by flash column chromatography (DCM/EA 50:1). General Procedure for the Products 2a−2t. To a mixture of substituted ureas 1 (0.25 mmol, 1 equiv), CuCl2·2H2O (0.05 mmol, 0.2 equiv) and Fe(NO3)3·9H2O (0.0875 mmol, 0.35 equiv) in toluene (3 mL) was added p-TSA (0.25 mmol, 1 equiv), then round-bottom flask was stirred at 110 °C temperature until TLC indicated the total consumption of the ureas. Upon completion, the mixture was treated with saturated NaHCO3 (10 mL) solution and extracted with DCM (3 × 10 mL). The combined organic phase was dried over Na2SO4 and then evaporated of the solvent under reduced pressure. Next,
purification of the crude residue by flash column chromatography on silica gel (PE/EA) afforded the desired products 2. Characterization Data of Products 2. 1,1-Dimethyl-3-(4methyl-2-nitrophenyl)urea (2a). The general procedure was followed using 0.29 mmol urea 1a. Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 54 mg, yield: 84%. mp: 102−103 °C. 1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.43 (d, J = 8.3 Hz, 1H), 3.12 (s, 6H), 2.37 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 154.7, 137.1, 135.4, 135.1, 131.3, 125.3, 121.2, 36.4, 20.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C10H13N3O3 224.1035; found 224.1033. 3-(4-Fluoro-2-nitrophenyl)-1,1-dimethylurea (2b). The general procedure was followed using 0.49 mmol urea 1b. Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 70 mg, yield: 63%. mp: 99− 100 °C. 1H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 8.63 (dd, J = 9.6, 5.4 Hz, 1H), 7.81 (dd, J = 8.4, 2.4 Hz, 1H), 7.19−7.31 (m, 1H), 3.02 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 155.8 (d, J = 243.7 Hz), 154.6, 134.1 (d, J = 2.3 Hz), 123.8 (d, J = 22 Hz), 123.2 (d, J = 7 Hz), 111.7 (d, J = 27 Hz), 36.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C9H10FN3O3 228.0784; found 228.0779. 3-(4-Chloro-2-nitrophenyl)-1,1-dimethylurea (2c). The general procedure was followed using 0.15 mmol urea 1c. Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 22 mg, yield: 61%. mp: 95−96 °C. 1H NMR (300 MHz, CDCl3) δ 10.15 (s, 1H), 8.73 (d, J = 9.3 Hz, 1H), 8.21 (t, J = 2.2 Hz, 1H), 7.57 (dd, J = 2.3, 9.3 Hz, 1H), 3.13 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.3, 136.2, 136.0, 135.5, 126.3, 125.1, 122.6, 36.5. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C9H10ClN3O3 244.0489; found 244.0481. 8318
DOI: 10.1021/acs.joc.8b01016 J. Org. Chem. 2018, 83, 8315−8321
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The Journal of Organic Chemistry
101.8, 56.6, 56.2, 36.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C11H15N3O5 270.1090; found 270.1086. 3-(4-Bromo-5-methoxy-2-nitrophenyl)-1,1-dimethylurea (2m). The general procedure was followed using 0.2 mmol urea 1m. Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 35 mg, yield: 59%. mp: 159−160 °C. 1H NMR (300 MHz, CDCl3) δ 10.66 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 4.03 (s, 3H), 3.15 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 161.8, 154.5, 139.6, 130.4, 128.8, 103.7, 101.7, 57.1, 36.5. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C10H12BrN3O4 318.0089; found 318.0083. 3-(3-Chloro-4-fluoro-2-nitrophenyl)-1,1-dimethylurea (2n). The general procedure was followed using 0.23 mmol urea 1n. Eluent: petroleum ether: ethyl acetate (16:1). Yellow solid, 20 mg, yield: 33%, mp: 145−146 °C. 1H NMR (300 MHz, CDCl3) δ 10.14 (s, 1H), 8.96 (d, J = 7.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 3.11 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.2, 151.4 (d, J = 246 Hz), 134.4 (d, J = 2.7 Hz), 130.6 (d, J = 18 Hz), 122.8, 112.7 (d, J = 26 Hz), 36.4. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C9H9ClFN3O3 262.0395; found 262.0390. 1-Ethyl-3-(4-methyl-2-nitrophenyl)urea (2q). The general procedure was followed using 0.26 mmol urea 1q. Eluent: petroleum ether: ethyl acetate (6:1). Yellow solid, 49 mg, yield: 78%, mp: 170−171 °C. 1 H NMR (300 MHz, CDCl3) δ 9.70 (s, 1H), 8.54 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 7.43 (d, J = 8.6 Hz, 1H), 5.02 (s, 1H), 3.40−3.36 (m, 2H), 2.37 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 154.3, 137.0, 135.2, 134.9, 131.3, 125.2, 121.5, 34.5, 20.3, 15.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C10H13N3O3 224.1035; found 224.1029. N-(4-Methyl-2-nitrophenyl)pyrrolidine-1-carboxamide (2s). Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 55 mg, yield: 90%, mp: 148−149 °C. 1H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.0 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 3.58− 3.54 (m, 4H), 2.37 (s, 3H), 2.03(s, 4H). 13C NMR (75 MHz, CDCl3) δ 153.0, 137.1, 135.2, 134.7, 131.1, 125.2, 121.1, 45.9, 25.6, 20.4, 15.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C12 H15 N3O3 250.1192; found 250.1179. N-(4-Methyl-2-nitrophenyl)morpholine-4-carboxamide (2t). The general procedure was followed using 0.23 mmol urea 1t. Eluent: petroleum ether: ethyl acetate (4:1). Yellow solid, 52 mg, yield: 87%, mp: 145−146 °C. 1H NMR (300 MHz, CDCl3) δ 10.14 (s, 1H), 8.52 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 3.79 (t, J = 4.5, 5.0 Hz, 3H), 3.59 (t, J = 4.5, 4.9 Hz, 3H), 2.38 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 153.9, 137.2, 135.5, 134.7, 131.8, 125.4, 121.4, 66.5, 44.1, 20.4, 15.1. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C12H15N3O4 266.1141; found 266.1130. Procedure for the Reduction of Compound 2a. To a solution of compound 2a (100 mg, 0.446 mmol) in MeOH (10 mL) was added 5% palladium−carbon catalyst (20 mg). The reaction mixture was allowed to stir at room temperature under H2. After 6 h, the mixture was filtered, concentrated in vacuo, and purified by column chromatography (petroleum ether/ethyl acetate 1:2) to give 74 mg (86%) of compound 3a as a purple solid. Data of Compound 3a. 3-(2-Amino-4-methylphenyl)-1,1dimethylurea. Purple solid, 74 mg, yield: 86%, mp: 42−43 °C. 1H NMR (300 MHz, CDCl3) δ 6.82 (d, J = 7.7 Hz, 1H), 6.49 (s, 1H), 6.47 (d, J = 7.7 Hz, 1H), 5.98 (s, 1H), 3.82 (s, 2H), 2.91 (s, 6H), 2.14 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.5, 141.5, 136.4, 125.7, 123.0, 120.2, 118.5, 36.6, 21.0. HRMS (ESI-QTOF) m/z: [M + H]+ calcd for C10H16N3O 194.1293; found 194.1284. Controlled Experiments. Reaction in the Presence of Radical Quencher TEMPO. To a mixture of substituted ureas 1 (0.25 mmol, 1 equiv), CuCl2·2H2O (0.05 mmol, 0.2 equiv), Fe(NO3)3·9H2O (0.0875 mmol, 0.35 equiv) and TEMPO (0.25 mmol, 1 equiv) in toluene (3 mL) was added p-TSA (0.25 mmol, 1 equiv), then roundbottom flask was stirred at 110 °C temperature. Upon completion, the mixture was treated with saturated NaHCO3 (10 mL) solution and extracted with DCM (3 × 10 mL). The combined organic phase was dried over Na2SO4 and then evaporated of the solvent under reduced pressure. Next, purification of the crude residue by flash column
3-(4-Bromo-2-nitrophenyl)-1,1-dimethylurea (2d). Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 54 mg, yield: 76%. mp: 103−105 °C. 1H NMR (300 MHz, CDCl3) δ 10.16 (s, 1H), 8.68 (d, J = 9.2 Hz, 1H), 8.36 (t, J = 2.3 Hz, 1H), 7.70 (dd, J = 2.2, 9.2 Hz, 1H), 3.13 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.3, 138.8, 136.6, 135.7, 128.0, 122.8, 113.1, 36.5. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C9H10BrN3O3 287.9984; found 287.9977. 3-(4-Iodo-2-nitrophenyl)-1,1-dimethylurea (2e). The general procedure was followed using 0.31 mmol urea 1e. Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 68 mg, yield: 65%. mp: 145− 146 °C. 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 8.54 (d, J = 9.1 Hz, 2H), 7.86 (d, J = 8.3 Hz, 1H), 3.13 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.2, 144.4, 137.2, 135.8, 133.9, 122.9, 82.2, 36.5. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C9H10IN3O3 335.9845; found 335.9839. 1,1-Dimethyl-3-(2-nitrophenyl)urea (2f). The general procedure was followed using 0.55 mmol urea 1f. Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 69 mg, yield: 60%. mp: 78−79 °C. 1H NMR (300 MHz, CDCl3) δ 10.2 (s, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 8.5, 7.3 Hz, 1H), 7.05 (t, J = 8.1, 7.6 Hz, 1H), 3.12 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.6, 137.4, 136.0, 135.5, 125.7, 121.3, 36.4. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C9H11N3O3 210.0879; found 210.0874. 3-(4-Methoxy-2-nitrophenyl)-1,1-dimethylurea (2g). The general procedure was followed using 0.46 mmol urea 1g. Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 100 mg, yield: 92%. mp: 120− 121 °C. 1H NMR (300 MHz, CDCl3) δ 9.97 (s, 1H), 8.60 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 2.7, 9.4 Hz, 1H), 3.85 (s, 3H), 3.11 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.9, 153.6, 135.9, 131.6, 124.5, 123.0, 107.6, 55.8, 36.4. HRMS (ESI-QTOF) m/ z [M + H]+ calcd for C10H13N3O4 240.0984; found 240.0985. 1,1-Dimethyl-3-(2-nitro-4-(trifluoromethyl)phenyl)urea (2h). Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 25 mg, yield: 35%. mp: above 300 °C. 1H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H), 8.80 (d, J = 8.9 Hz, 1H), 8.38 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 3.02 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.0, 140.2, 134.4, 132.1 (d, J = 3.2 Hz), 124.8, 123.5 (t, J = 4.2 Hz), 122.1 (t, J = 138 Hz), 121.8, 36.5. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C10H10F3N3O3 278.0753; found 278.0749. Methyl-4-(3,3-dimethylureido)-3-nitrobenzoate (2i). The general procedure was followed using 0.36 mmol urea 1i. Eluent: petroleum ether: ethyl acetate (12:1). Yellow solid, 37 mg, yield: 38%. mp: 152− 153 °C. 1H NMR (300 MHz, CDCl3) δ 10.48 (s, 1H), 8.92 (s, 1H), 8.85 (d, J = 9.1 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 3.96 (s, 3H), 3.16 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 165.0, 154.0, 140.8, 136.3, 127.8, 123.0, 120.7, 52.5, 36.5. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C11H13N3O5 290.0753; found 290.0749. 3-(2-Methoxy-6-nitrophenyl)-1,1-dimethylurea (2j). The general procedure was followed using 0.75 mmol urea 1j. Eluent: petroleum ether: ethyl acetate (16:1). Yellow solid, 90 mg, yield: 50%. mp: 126− 127 °C. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.71 (s, 1H), 7.38 (s, 1H), 3.98 (s, 3H), 3.07 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 154.4, 146.6, 141.6, 118.1, 116.7, 104.9, 56.4, 36.4. HRMS (ESI-QTOF) m/z [M + H]+ calcd for C10H13N3O4 240.0984; found 240.0981. 3-(5-Methoxy-2-nitrophenyl)-1,1-dimethylurea (2k). The general procedure was followed using 0.49 mmol urea 1k. Eluent: petroleum ether: ethyl acetate (8:1). Yellow solid, 59 mg, yield: 50%. mp: 151− 153 °C. 1H NMR (300 MHz, CDCl3) δ 10.72 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 9.6 Hz, 1H), 6.58 (dd, J = 2.3, 9.7 Hz, 1H), 3.93 (s, 3H), 3.14 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 165.8, 154.8, 140.5, 128.7, 128.0, 110.2, 102.1, 56.0, 36.4. HRMS (ESI-QTOF) m/ z: [M + H]+ calcd for C10H13N3O4 240.0984; found 240.0983. 3-(4,5-Dimethoxy-2-nitrophenyl)-1,1-dimethylurea (2l). The general procedure was followed using 0.45 mmol urea 1l. Eluent: petroleum ether: ethyl acetate (12:1). Yellow solid, 67 mg, yield: 55%, mp: 172−173 oC. 1H NMR (300 MHz, CDCl3) δ 10.72 (s, 1H), 8.51 (s, 1H), 7.69 (s, 1H), 4.03 (s, 3H), 3.94 (s, 3H), 3.14 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 156.3, 155.0, 143.4, 135.2, 127.4, 106.7, 8319
DOI: 10.1021/acs.joc.8b01016 J. Org. Chem. 2018, 83, 8315−8321
Article
The Journal of Organic Chemistry chromatography on silica gel (petroleum ether: ethyl acetate 8:1) afforded the desired product 2a in a yield of 53%. Intermolecular Competition Reaction between 1g and 1i. To a mixture of urea 1g (0.15 mmol), 1i (0.15 mmol), CuCl2·2H2O (0.06 mmol, 0.2 equiv) and Fe(NO3)3·9H2O (0.105 mmol, 0.35 equiv) in toluene (3 mL) was added p-TSA (0.3 mmol, 1 equiv), then round-bottom flask was stirred at 110 °C temperature. Upon completion, the mixture was treated with saturated NaHCO3 (10 mL) solution and extracted with DCM (3 × 10 mL). The combined organic phase was dried over Na2SO4 and then evaporated of the solvent under reduced pressure. Next, the mixed products 2g and 2i were separate through the purification of the crude residue with flash column chromatography on silica gel (petroleum ether: ethyl acetate 8:1). The ratio of 2g and 2i was determined by 1H NMR, which showed the result was 1:1. Preparation of Phenyl Dimethylcarbamate 4. The substrate 4 was prepared according to literature reported method.13 Nitration of Phenyl Dimethylcarbamate 4. To a mixture of compound 4 (41 mg, 0.25 mmol, 1 equiv), CuCl2·2H2O (0.05 mmol, 0.2 equiv) and Fe(NO3)3·9H2O (0.0875 mmol, 0.35 equiv) in toluene (3 mL) was added p-TSA (0.25 mmol, 1 equiv), then round-bottom flask was stirred at 110 °C temperature for 10 h, and there was no reaction proceeding.
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anilinoquinazoline-urea Derivatives as Dual TK Inhibitors of EGFR and VEGFR-2. Eur. J. Med. Chem. 2017, 125, 245−254. (2) (a) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. Cationic Palladium (II) Catalysis: C−H Activation/Suzuki−Miyaura Couplings at Room Temperature. J. Am. Chem. Soc. 2010, 132, 4978− 4979. (b) Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Room Temperature C-H Activation and Cross-Coupling of Aryl Ureas in Water. Angew. Chem., Int. Ed. 2010, 49, 781−784. (c) Jiang, Z.; Zhang, L.; Dong, C.; Su, X.; Li, H.; Tang, W.; Xu, L.; Fan, Q. Direct Synthesis of 8-Aryl tetrahydroquinolines via Pd-Catalyzed orthoArylation of Aryl Ureas in Water. RSC Adv. 2013, 3, 1025−1028. (d) Jiang, P.; Li, F.; Xu, Y.; Liu, Q.; Wang, J.; Ding, H.; Yu, R.; Wang, Q. Aromaticity-Dependent Regioselectivity in Pd(II)-Catalyzed C-H Direct Arylation of Aryl Ureas. Org. Lett. 2015, 17, 5918−5921. (3) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. RoomTemperature Palladium-Catalyzed C-H Activation: ortho-Carbonylation of Aniline Derivatives. Angew. Chem., Int. Ed. 2009, 48, 1830− 1833. (4) (a) Rauf, W.; Thompson, A. L.; Brown, J. M. Comparative Catalytic C-H vs C-Si Activation of Arenes with Pd Complexes Directed by Urea or Amide Groups. Chem. Commun. 2009, 3874− 3876. (b) Nishikata, T.; Lipshutz, B. H. Cationic Pd(II)-Catalyzed Fujiwara−Moritani Reactions at Room Temperature in Water. Org. Lett. 2010, 12, 1972−1975. (c) Willwacher, J.; Rakshit, S.; Glorius, F. Investigating N-methoxy-N’-aryl Ureas in Oxidative C-H Olefination Reactions: An Unexpected Oxidation Behaviour. Org. Biomol. Chem. 2011, 9, 4736−4740. (d) Jiang, P.; Xu, Y.; Sun, F.; Liu, X.; Li, F.; Yu, R.; Li, Y.; Wang, Q. Pd(II)-Catalyzed ortho-C-H Olefination/ Dearomatization of N-Aryl Ureas: An Approach to Imine Derivatives. Org. Lett. 2016, 18, 1426−1429. (5) (a) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagné, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Distinct Reactivity of Pd(OTs)2: The Intermolecular Pd(II)-Catalyzed 1,2-Carboamination of Dienes. J. Am. Chem. Soc. 2008, 130, 10066−10067. (b) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. The Vinyl Moiety as A Handle for Regiocontrol in the Preparation of Unsymmetrical 2,3Aliphatic-Substituted Indoles and Pyrroles. Angew. Chem., Int. Ed. 2011, 50, 1338−1341. (c) Kovács, S.; Tóth, B. L.; Borsik, G.; Bihari, T.; May, N. V.; Stirling, A.; Novák, Z. Direct ortho-Trifluoroethylation of Aromatic Ureas by Palladium Catalyzed C-H Activation: A Missing Piece of Aromatic Substitutions. Adv. Synth. Catal. 2017, 359, 527− 532. (6) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001. (b) Feuer, H.; Nielsen, A. T. Nitro Compounds:Recent Advances in Synthesis and Chemistry; Wiley-VCH: New York, 1990. (7) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods and Mechanisms; Wiley-VCH: Weinheim, 1989. (8) For selective examples, see: (a) Prakash, G. K. S.; Panja, C.; Mathew, T.; Surampudi, V.; Petasis, N. A.; Olah, G. A. ipso-Nitration of Arylboronic Acids with Chlorotrimethylsilane−Nitrate Salts. Org. Lett. 2004, 6, 2205−2207. (b) Saito, S.; Koizumi, Y. CopperCatalyzed Coupling of Aryl Halides and Nitrite Salts: A Mild Ullmann-type Synthesis of Aromatic Nitro Compounds. Tetrahedron Lett. 2005, 46, 4715−4717. (c) Fors, B. P.; Buchwald, S. L. PdCatalyzed Conversion of Aryl Chlorides, Triflates, and Nonaflates to Nitroaromatics. J. Am. Chem. Soc. 2009, 131, 12898−12899. (d) Prakash, G. K.; Mathew, T. ipso-Nitration of arenes. Angew. Chem., Int. Ed. 2010, 49, 1726−1728. (9) (a) Liu, Y.-K.; Lou, S.-J.; Xu, D.-Q.; Xu, Z.-Y. Regiospecific Synthesis of Nitroarenes by Palladium-Catalyzed Nitrogen-DonorDirected Aromatic C-H Nitration. Chem. - Eur. J. 2010, 16, 13590− 13593. (b) Zhang, W.; Lou, S.; Liu, Y.; Xu, Z. Palladium-Catalyzed Chelation-Assisted Aromatic C−H Nitration: Regiospecific Synthesis of Nitroarenes Free from the Effect of the Orientation Rules. J. Org. Chem. 2013, 78, 5932−5948. (c) Zhang, W.; Zhang, J.; Ren, S.; Liu, Y. Palladium-Catalyzed Aromatic C-H Bond Nitration Using Removable Directing Groups: Regiospecific Synthesis of Substituted
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01016. Copies of 1H and 13C NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected];
[email protected]. ORCID
Li-Ping Sun: 0000-0002-3716-3108 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the funds supported by the National Natural Science Foundation (NO. 21472243), Jiangsu Provincial Natural Science Foundation, the National College Students Innovation Training Program and Technology Innovation Team of Jiangsu Province in 2015 China.
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REFERENCES
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DOI: 10.1021/acs.joc.8b01016 J. Org. Chem. 2018, 83, 8315−8321
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DOI: 10.1021/acs.joc.8b01016 J. Org. Chem. 2018, 83, 8315−8321
