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Sep 19, 2017 - College of Biotechnology and bioengineering, Zhejiang University of Technology, Hangzhou 310014, China. ‡. Department of Biology and ...
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Regioselective and Direct Azidation of Anilines via Cu(II)-Catalyzed C−H Functionalization in Water Hongli Fang,† Yandong Dou,† Jingyan Ge,† Mohit Chhabra, Hongyan Sun,‡ Pengfei Zhang,§ Yuguo Zheng,*,† and Qing Zhu*,† †

College of Biotechnology and bioengineering, Zhejiang University of Technology, Hangzhou 310014, China Department of Biology and Chemistry, City University of Hong Kong, Hong Kong, China § College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China ‡

S Supporting Information *

ABSTRACT: We report herein the first example of Cu(II)-catalyzed site selective azidation of aromatic amines via C−H functionalization in aqueous media. In our strategy, a mild reagent was utilized. H2O2 served as the oxidant, and sodium azide was used as the azidation reagent. This method could also be applied to late-stage functionalization of drugs that possess an aromatic amine moiety. In addition, we found that bromination or iodination on the ortho-position of aromatic amines could occur efficiently using this catalytic system.

D

Scheme 1. Aryl Azidation via C−H Activations

uring the past few years, the formation of C−N bonds, especially the azidation of the aromatic compounds, has attracted increasing attention from researchers.1 For example, the high synthetic versatility of azide has given organoazides important roles in organic/medicinal chemistry.2 Azides are ubiquitously employed in Huisgen 1,3-dipolar cycloaddition (“click”) reactions.3 The introduction of azide in drug molecules has found wide applications in activity-based protein profiling (ABPP) based on click chemistry.4 The increasing need for biological and medicinal chemistry has therefore driven rapid development in efficient and biocompatible azidation methodology. The conventional approaches include nucleophilic substitution of C−X bonds, the Mitsunobu reaction from alcohols, the Michael addition of CC bond, or transformations from hydrazines, triazenes, and nitrosoarenes. However, all these original functional groups are sometimes extremely important for retaining their biological activity. Direct azidation through the activation of a C−H bond, an ubiquitous bond present in all organic molecules, provides an ideal methodology to avoid the loss of important functional groups.5 This type of reaction could also be employed at a late stage, thereby providing a straightforward and atom-economical way to build new libraries of compounds of interest.6 For example, aryl azides display high stability, and they have been widely used for the photoaffinity labeling of biological compounds and improvement of bioactivity via azide functionality.7 Unfortunately, to date, there have been few reported examples of direct azidation on the aromatic ring via C−H activation except an article by Jiao et al. that disclosed a Cu(I)-catalyzed ortho-azidation of anilines utilizing TMS-N3 as the azide reagent and tert-butyl hydroperoxide (TBHP) as the oxidant (Scheme 1A).5 To improve the regioselectivity of azidation, the amine group was employed as the directing group in the reaction. However, the reaction does not give a single azidation © 2017 American Chemical Society

product when the p-aniline derivatives were chosen as the reactant. Double ortho-azidations of anilines and its derivatives are obtained. J. Hao et al. developed the Cu(II)-catalyzed regioselective aromatic C−H azidation method (Scheme 1B).8 In their approach, the primary amine exhibited an excellent ortho-directing effect, producing ortho-azidated anilines as the sole products. Nevertheless, THF was used as solvent, and it is not environmentally friendly. Furthermore, the use of organic solvent in these reactions hinders the practical applications of this methodology. Therefore, it is highly desirable to develop an environmentally Received: July 12, 2017 Published: September 19, 2017 11212

DOI: 10.1021/acs.joc.7b01594 J. Org. Chem. 2017, 82, 11212−11217

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The Journal of Organic Chemistry Table 1. Cu(II)-Catalyzed Azidation of Anilinesa

benign, regioselective, and biocompatible azidation via C−H activation reaction. Based on our previous study9 of the remote C−H azidation of quinolones and the necessity of the construction of the drug library containing aromatic amines, herein we report a regioselective, Cu(II)-catalyzed C−H azidation reaction of aniline derivatives under extremely mild conditions (Scheme 1C). This methodology is distinctly superior in the following aspects. First, direct azidation in water and even in the presence of proteins has not been achieved until this work. Together with the water-soluble azidation source NaN3 and mild oxidant H2O2, these mild and green reaction conditions can facilitate its broad applications in medicinal chemistry and chemical biology. Second, compared with the reported C−H bond azidation, our process exhibits high regioselectivity on the aromatic ring, providing the single ortho-azidated product. Lastly, this highly efficient copper-catalyzed functionalization protocol can be further expanded to the construction of a variety of other chemical bonds, including C−Br and C−I bonds. We first examined the azidation of aniline (1a) under an aqueous medium using TBHP as the model reaction. NaN3, an easily available and inexpensive azidation source, was chosen as the azidation reagent. To comply with the principle of green chemistry and biological chemistry, water was chosen as the reaction medium. However, under the literature conditions,5 only a 32% yield of the desired product was obtained, which may be due to the poor water solubility of CuBr (Table S1, entry 1). To improve the yield of ortho-azidation of aniline, we next screened different catalysts. Considering that Cu(OAc)2 shows good water solubility and causes less damage to biological systems, we tested it together with the other transition metal halides, including CuBr2 and FeCl3. To our delight, Cu(OAc)2 showed superior catalytic activity, affording the highest yield (54%) of compound 2a, whereas FeCl3 and Pd(OAc)2 did not give the desired product (Table S1, entries 2−5). Surprisingly, in comparison with the reported method,5 this reaction shows better site selectivity and no diazidation compound was observed. Inspired by these results, we moved on to search for a suitable oxidant for this reaction. The choice of oxidant is critical for radical-mediated C−H bond activation reactions. Generally, K2S2O8, (NH4)2S2O8, or MnO2 is used as the oxidant. However, these compounds require tedious postprocessing operations.6a,10 Only a few examples of H2O2 as an efficient oxidant have been reported. Considering it is a green and easily removable reagent, it was examined as an oxidant under the above-mentioned conditions. Surprisingly, it was found that H2O2 displayed higher oxidation activity than other oxidants do, and the yield was increased to 78% (Table S1, entries 6−8). Next, to evaluate whether additives will affect the reaction, various salts, including K2CO3, NaCl, and NaHCO3, were added. The yield, however, reduced significantly when additives were added (entries 9−11). Lastly, to validate whether H2O is the best solvent for direct azidation via C−H activation, different solvents, such as H2O, DMF, DCM, and MeCN, were also examined. It was found that, in the presence of sodium salt (NaN3), H2O2, and Cu(OAc)2, 2-azidoaniline (2a) was obtained in 78% yield in H2O at room temperature (Table S1, entry 6). More importantly, there was no diazide product observed by GCMS. Having established the optimal azidation conditions of aniline, we further explored the scope of this methodology with various aniline derivatives, and the results are summarized in Table 1. It is clearly shown that the halogenated aniline can be converted

a

Reaction conditions: 1a (0.2 mmol), NaN3 (2.0 equiv), Cu(OAc)2 (0.25 equiv), H2O2 (2.0 equiv), H2O (2 mL), rt, air. Note that the yields shown here are isolated yields.

to the corresponding azides (2b−2f) in good yields (52%−66%), demonstrating that the halogens could be tolerant under the reaction conditions. Meanwhile, aniline derivatives with aliphatic substituents (2j−2p) gave high yields (58%−84%), while anilines bearing a linear alkyl group showed higher activity (2j−2n) than alicyclic anilines (2o, 2p). In the presence of a pyridine substituent, 7-azido-8-amine-quinoline (2q) is obtained in 45% yield. We found that quinoline is also compatible with this methodology, and it gave the desired product 2r in 54% yield. The o-phenyl substituent, [1,1′-biphenyl]-2-amine (1t), afforded the corresponding product 2t in 45% yield. In addition, electron-withdrawing (2b−2i) and electron-donating (2j−2n) groups on the aryl ring are all tolerant to the reaction. Furthermore, the ortho-substituted aniline (2j−2n) can afford the desired products in good yields (60%−84%), while the para-substituted aniline is also a suitable substrate for this reaction, affording product 2g−2i in 55%−75% yield. Moreover, secondary aniline derivative 1v is able to yield the desired product 2v in 51% yield under the same reaction conditions. To establish the versatility of this site-specific C−H azidation, three drugs bearing aniline, namely procaine, benzocaine, and aminoglutethimide, were employed as substrates (Scheme 2). The monoazidation products were successfully obtained in 61%, 65%, and 60% yield, respectively. These results suggested that C(sp2)−H azidation is applicable to late-stage functionalization of complex molecules. To verify whether the reaction could 11213

DOI: 10.1021/acs.joc.7b01594 J. Org. Chem. 2017, 82, 11212−11217

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The Journal of Organic Chemistry

employed as a radical acceptor (Scheme 3), the radical intercepted product m was detected, indicating that an azido radical is involved in the reaction. The Binding Energy (BE) peak at 943.2 eV indicated the presence of Cu2+.12 The BE peak at 933.1 eV suggests the presence of Cu+ or Cu(0) species.12a,13 Because Cu 2p3/2 XPS cannot differentiate between Cu+ and Cu(0), Cu LMM spectra were used to confirm the presence of Cu+ at BE 570.9 eV (Figure S2).14 Based on our present work and previous reports,5 a mechanistic hypothesis for the Cu(II)-catalyzed C−H azidation of anilines with NaN3 has been proposed in Scheme 4. First, the aniline

Scheme 2. Azidation of Aniline-Based Drugs

occur in a biological environment, the azidation of Procaine was carried out in the presence of proteins. Results showed that the reaction could successfully occur when cell lysate (1 mg/mL proteins) was added. A slight increase in the yield from 65% to 70% was observed. To determine the applicability of this reaction approach to other functionalizations of anilines, we performed the synthesis of ortho-halogenated anilines using the above catalyst system. To our delight, the ortho C−H directed halogenations, except for chlorination, could be successfully achieved in the presence of the copper(II) catalyst. The corresponding brominated and iodinated products were obtained in 27−55% yields with the recovery of 35−55% of reactants (Table 2). To the best of our

Scheme 4. Proposed Mechanism for Cu(II) Catalyzed C−H Azidation of Anilines

Table 2. Cu(II)-Catalyzed Halogenations of Anilinesa

forms anilines−Cu(II) complex A under the catalysis of Cu(OAc)2. The complex formed is then attacked by the radical, which is generated from NaN3 and H2O2, to afford complex B.15 Subsequently, a single electron transfer (SET) from the aryl ring to the metal center (B → C) occurs. The azide group subsequently transfers to the ortho-position of aniline via a metal dissociation process and forms intermediate D. Finally, the target product 2a is obtained through the SET process. To validate the application of the ortho-azidation of anilines, two reactions including a click reaction and reduction, were performed using azidated aminoglutethimide (2y) as the substrate (Scheme 5). The click reaction between compound 2y and

a

Reaction conditions: 1a (0.2 mmol), halogenation reagents (2.0 equiv), Cu(OAc)2 (0.25 equiv), H2O2 (2.0 equiv), H2O (2 mL), rt, air. Note that the yields shown here are GC yields.

knowledge, few catalytic systems in a C−H activation could be applied to the formation of C−H azidation as well as C−I and C−Br bonds under similar conditions.11 Preliminary study on the reaction mechanism was further conducted using 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as the radical scavengers in the azidation of aniline with NaN3. As shown in Scheme 3, the azidation reaction was completely quenched, indicating that the reaction involves a radical process. Moreover, when 1,1-diphenylethylene was

Scheme 5. Typical Transformations of 2y

Scheme 3. Mechanism Investigation

2-butyl-6-ethynyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (7) was performed successfully in the presence of 1.2 equiv of CuSO4 and Vitamin C (Vc), and the corresponding triazole 5 was obtained in 81% yield. Encouraged by the above-mentioned results, we further evaluated the applicability of 2y by a live cell imaging study using confocal laser scanning microscopy (CLSM). The imaging experiment was carried out based on the turn-on imaging strategy to reduce the background from the fluorophores, as illustrated in Scheme 5. Alkynyl substituted naphthalimide 7 11214

DOI: 10.1021/acs.joc.7b01594 J. Org. Chem. 2017, 82, 11212−11217

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The Journal of Organic Chemistry is a nonfluorescent dye that can generate a highly fluorescent signal upon the formation of triazole via click reaction with azidated compound 2y. HepG-2 cells were chosen in our experiments. As shown in Figure 1, when HepG-2 cells were incubated with 2y (20 μM), 7 (20 μM), CuSO4 (20 μM), and Vitamin C

apparatus using CDCl3 as the solvent, and the frequencies measuring 1 H, 13C NMR were 126 MHz. Chemical shifts were recorded in ppm by employing TMS (for 1H NMR) or the solvent peak of CDCl3 (77.0 ppm, for 13C NMR) as an internal standard. High resolution mass spectra (HRMS) (ion trap) were measured using electrospray ionization (ESI) mass spectrometry. General Procedure for the Azidation of Aniline and Its Derivatives. A 25 mL single-neck flask was equipped with a magnetic stir bar and charged with aniline 1a (0.5 mmol), NaN3 (1.0 mmol, 2 equiv), H2O2 (1.0 mmol, 2 equiv), Cu(OAc)2 (0.125 mmol, 25 mol %), and H2O (5 mL). The mixture was stirred at room temperature for 2 h as monitored by TLC and poured into water (25 mL). The mixture was then extracted with ethyl acetate three times and washed with H2O three times. The combined organic layer was subsequently dried over anhydrous Mg2SO4 and filtered. After the solvent was evaporated under vacuum, the crude product was purified by silica gel column chromatography (EtOAc/petroleum ether) to afford the product 2a. 2-Azidoaniline (2a).5 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 2a (42 mg, 69%) as a light brown solid. 1H NMR (500 MHz, CDCl3) δ 7.04 (dd, J = 7.9, 1.2 Hz, 1H), 6.97 (td, J = 7.7, 1.3 Hz, 1H), 6.80 (td, J = 7.7, 1.3 Hz, 1H), 6.70 (dd, J = 7.9, 1.3 Hz, 1H), 3.81 (s, 2H).13C NMR (126 MHz, CDCl3) δ 146.33, 129.20, 118.43, 115.02. 2-Azido-6-bromoaniline (2b).16 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:50) to afford 2b (67 mg, 63%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 6.90 (d, J = 2.1 Hz, 1H), 6.88−6.81 (m, 1H), 6.66 (t, J = 7.9 Hz, 1H), 3.84 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 147.8, 130.5, 122.9, 121.2, 117.7, 113.6. 2-Azido-3-bromoaniline (2c).17 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:55) to afford 2c (69 mg, 65%) as a dark brown oil. 1H NMR (500 MHz, CDCl3) δ 6.91−6.86 (m, 2H), 6.83 (d, J = 1.3 Hz, 1H), 3.88 (s, 2H). 13 C NMR (126 MHz, CDCl3) δ 147.77, 130.56, 122.96, 121.26, 117.74, 113.58. 2-Azido-3-chloroaniline (2d).18 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:40) to afford 2d (55 mg, 66%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 6.92 (d, J = 8.4 Hz, 1H), 6.74 (dd, J = 8.3, 2.3 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 3.88 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 147.61, 134.70, 130.25, 118.31, 114.82, 113.14. 2-Azido-4-fluoroaniline (2e).8 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:40) to afford 2e (40 mg, 52%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 6.78 (dd, J = 8.8, 2.7 Hz, 1H), 6.68 (dd, J = 7.7, 3.2 Hz, 1H), 6.63 (dd, J = 8.7, 5.2 Hz, 1H), 3.66 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 157.31, 142.38, 116.05, 115.99, 115.71, 115.53. 2-Azido-4-chloro-6-methylaniline (2f).8 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:35) to afford 2f (55 mg, 60%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 6.90 (s, 1H), 6.85 (s, 1H), 3.74 (s, 2H), 2.13 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 143.13, 129.96, 126.59, 123.92, 122.81, 115.85, 17.21. Methyl 4-Amino-3-azidobenzoate (2g).5 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:15) to afford 2g (54 mg, 56%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.3, 1.7 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 4.23 (s, 2H), 3.88 (s, 3H).13C NMR (126 MHz, CDCl3) δ 167.18, 150.91, 131.53, 119.49, 113.72, 51.54. 2-Azido-4-methoxyaniline (2h).8 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:10) to afford 2h (45 mg, 55%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 6.67 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 6.57 (dd, J = 8.6, 2.7 Hz, 1H), 3.78 (s, 3H), 3.56 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 152.71, 139.93, 116.34, 114.75, 55.66. 2-Azido-4-(trifluoromethoxy)aniline (2i). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:25) to afford 2i (82 mg, 75%) as a brown solid. 1H NMR

Figure 1. Reactivity of 2y for CuAAC reaction in live cells. a1−a3: HepG-2 cells were treated with DMSO (0.1%). b1−b3: HepG-2 cells were treated with 2y (20 μM), 7 (20 μM) in the absence of CuSO4 for 15 min. c1−c3: HepG-2 cells were treated with a mixture of 2y (20 μM), 7 (20 μM), and Vitamin C (50 μM) in the presence of CuSO4 (20 μM) for 15 min. d1−d3: Cells treated with probe 5 only. The excitation wavelength was set at 405 nm. The emission was collected between 420 and 500 nm.

(50 μM) in DMEM for 15 min, it showed strong fluorescence (Figure 1c) due to the formation of compound 5 after the click reaction. The results are in agreement with the results from the cells treated with compound 5 only (Figure 1d). The cells incubated with 0.1% DMSO only (Figure 1a), or with 2y (20 μM), 7 (20 μM) in the absence of CuSO4 (Figure 1b), were used as negative controls. It is not surprising that only negligible fluorescence could be observed, further confirming that the fluorescence increase was due to the formation of 5. These results indicated that azidated drugs can be employed to further study the mechanisms of drug effect in living cells.

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CONCLUSION We have developed a novel and efficient Cu(II)-catalyzed orthoazidation of anilines via C−H activation. This methodology shows a broad substrate scope and high site specificity. More importantly, the azidation works well at the ambient temperature in water and even in the presence of cell lysate, indicating the approach is likely to have wide application in biological systems. A free radical cross-coupling reaction mechanism was further proposed. Moreover, the reaction can be expanded to the fast formation of a variety of chemical bonds, including C−Br and C−I. The convenient transformation of 2y to amines and triazoles further widen the application of this methodology.

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EXPERIMENTAL SECTION

General Considerations. All reactions were performed open to air. All chemicals were obtained from commercial sources and used directly without further purification. Solvents used in the experiment have been prior treated following a standard procedure. The reaction process was monitored by TLC. The NMR was recorded in a 500 MHz 11215

DOI: 10.1021/acs.joc.7b01594 J. Org. Chem. 2017, 82, 11212−11217

Note

The Journal of Organic Chemistry (500 MHz, CDCl3) δ 6.90 (d, J = 2.1 Hz, 1H), 6.84 (dd, J = 8.3, 2.9 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 3.84 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 145.32, 141.30, 123.77, 122.38, 121.74, 119.71, 115.48. HRMS (ESI-ion trap) m/z: Calculated for C7H6F3N4O: [M + H]+ 219.0415, found 219.0421. 2-Azido-4,6-dimethylaniline (2j).8 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 2j (68 mg, 84%) as a light brown solid. 1H NMR (500 MHz, CDCl3) δ 6.74 (s, 1H), 6.69 (s, 1H), 3.62 (s, 2H), 2.25 (s, 3H), 2.13 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 141.90, 130.95, 127.55, 127.17, 122.25, 114.94, 20.26, 17.12. 2-Azido-3,6-dimethylaniline (2k). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:35) to afford 2k (66 mg, 81%) as a light brown solid. 1H NMR (500 MHz, CDCl3) δ 6.82 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 3.87 (s, 2H), 2.37 (s, 3H), 2.14 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 144.29, 136.44, 130.18, 119.26, 115.63, 20.92, 16.72. HRMS (ESI-ion trap) m/z: Calculated for C8H11N4: [M + H]+ 163.0905, found 163.0913. 2-Azido-6-ethylaniline (2l).8 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:50) to afford 2l (65 mg, 80%) as a brown liquid. 1H NMR (500 MHz, CDCl3) δ 6.94 (dd, J = 7.9, 1.2 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.77 (t, J = 7.7 Hz, 1H), 3.80 (s, 2H), 2.51 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 143.94, 128.29, 128.00, 126.74, 118.74, 115.31, 23.92, 12.93. 2-Azido-6-propylaniline (2m). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:20) to afford 2m (67 mg, 76%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 6.93 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.75 (t, J = 7.7 Hz, 1H), 3.87 (s, 2H), 2.48−2.43 (m, 2H), 1.64 (dd, J = 15.1, 7.5 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 144.06, 129.47, 126.73, 118.63, 115.48, 115.43, 33.32, 21.83, 14.13. HRMS (ESI-ion trap) m/z: Calculated for C9H13N4: [M + H]+ 177.1062, found 177.1069. 2-Azido-6-(tert-butyl)aniline (2n).5 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:15) to afford 2n (57 mg, 60%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 7.05 (dd, J = 8.0, 1.3 Hz, 1H), 6.96 (dd, J = 7.9, 1.3 Hz, 1H), 6.76 (t, J = 7.9 Hz, 1H), 4.08 (s, 2H), 1.41 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 144.56, 133.62, 126.91, 126.47, 118.58, 117.71, 34.20, 29.53. 2-Azido-5,6,7,8-tetrahydronaphthalen-1-amine (2o). The crude product was purified by silica gel column chromatography (EtOAc/ petroleum ether = 1:40) to afford 2o (61 mg, 65%) as a brown solid. 1 H NMR (500 MHz, CDCl3) δ 6.84 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 3.73 (s, 2H), 2.71 (t, J = 6.1 Hz, 2H), 2.43 (t, J = 6.5 Hz, 2H), 1.87−1.83 (m, 2H), 1.76−1.72 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 144.20, 137.94, 125.80, 121.66, 119.43, 112.04, 29.87, 23.93, 23.03, 22.71. HRMS (ESI-ion trap) m/z: Calculated for C10H13N4: [M + H]+ 189.1062, found 189.1075. 5-Azido-2,3-dihydro-1H-inden-4-amine (2p). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 2p (51 mg, 58%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 6.88 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 3.72 (s, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.13 (p, J = 7.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 145.36, 142.43, 128.61, 127.34, 114.72, 112.28, 33.17, 29.31, 24.61. HRMS (ESI-ion trap) m/z: Calculated for C9H11N4: [M + H]+ 175.0905, found 175.0911. 7-Azido-8-amine-quinolin (2q). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 2q (42 mg, 45%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 8.76 (dd, J = 4.2, 1.6 Hz, 1H), 8.05 (dd, J = 8.3, 1.6 Hz, 1H), 7.33 (dd, J = 8.3, 4.2 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 5.05 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 147.38, 143.93, 138.38, 135.93, 128.81, 127.33, 121.28, 115.97, 109.99. HRMS (ESI-ion trap) m/z: Calculated for C9H8N5: [M + H]+ 186.0701, found 186.0713.

2-Azidonaphthalen-1-amine (2r).8 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 2r (46 mg, 50%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 7.6 Hz, 2H), 7.86 (d, J = 7.3 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 7.7 Hz, 2H), 5.25 (s, 2H) . 13C NMR (126 MHz, CDCl3) δ 142.04, 134.33, 128.49, 126.30, 125.79, 124.78, 123.58, 120.76, 118.88, 109.62. 1-(6-Amino-7-azidonaphthalen-2-yl)ethanone(2s). The crude product was purified by silica gel column chromatography (EtOAc/ petroleum ether = 1:50) to afford 2s (68 mg, 60%) as a brown solid. 1 H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.00 (dd, J = 8.9, 1.7 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 4.94 (s, 2H), 2.68 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 198.02, 134.32, 131.67, 130.35, 130.05, 129.78, 127.80, 125.24, 124.16, 123.60, 118.20, 26.56. HRMS (ESI-ion trap) m/z: Calculated for C12H11N4O: [M + H]+ 227.0855, found 227.0849. 3-Azido-[1,1-biphenyl]-2-amine (2t).5 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:60) to afford 2t (47 mg, 45%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 7.46−7.41 (m, 4H), 7.38−7.34 (m, 1H), 7.05 (dd, J = 7.9, 1.4 Hz, 1H), 6.94 (dd, J = 7.6, 1.4 Hz, 1H), 6.85 (t, J = 7.7 Hz, 1H), 3.94 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 143.53, 139.56, 130.48, 129.12, 128.84, 128.52, 127.65, 127.19, 118.66, 115.62. (4-Amino-3-azidophenyl)(phenyl)methanone (2u). The crude product was purified by silica gel column chromatography (EtOAc/ petroleum ether = 1:90) to afford 2u (58 mg, 49%) as a dark brown solid. 1H NMR (500 MHz, CDCl3) δ 7.73 (dd, J = 4.9, 3.4 Hz, 2H), 7.58−7.54 (m, 1H), 7.47 (t, J = 7.6 Hz, 3H), 7.43 (dd, J = 8.3, 1.8 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 4.45 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 194.6, 148.3, 142.8, 250.5−129.3 (m), 138.3, 138.6−131.5 (m), 133.3 (dd, J = 438.1, 432.2 Hz), 128.2 (d, J = 5.0 Hz), 124.9, 120.4, 114.0, 113.6. HRMS (ESI-ion trap) m/z: Calculated for C13H11N4O: [M + H]+ 239.0856, found 227.0858. 2-Azido-N-phenylaniline (2v). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:60) to afford 2v (54 mg, 51%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 7.35−7.29 (m, 3H), 7.17−7.12 (m, 3H), 7.08−7.00 (m, 2H), 6.94 (td, J = 7.7, 1.3 Hz, 1H), 5.96 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 141.9, 135.2, 129.4, 129.1, 127.2, 125.4, 122.0, 120.6, 119.2, 118.5, 118.1, 115.7. HRMS (ESI-ion trap) m/z: Calculated for C12H11N4: [M + H]+ 211.0905, found 211.0910. Ethyl 4-Amino-3-azidobenzoate (2w).8 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 2w (63 mg, 61%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 8.3, 1.8 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.40−4.33 (m, 2H), 4.24 (s, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.72, 150.82, 131.49, 119.92, 113.71, 60.26, 14.37. 2-(Diethylamino)ethyl 4-Amino-3-azidobenzoate (2x). The crude product was purified by silica gel column chromatography (EtOAc/ petroleum ether = 1:40) to afford 2x (90 mg, 65%) as a brown solid. 1 H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 4.52 (t, J = 5.7 Hz, 2H), 4.29 (s, 2H), 3.06 (s, 2H), 2.86 (d, J = 6.9 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 165.73, 142.79, 127.97, 124.73, 119.92, 119.75, 114.29, 50.54, 47.67, 29.70, 28.61, 10.86, 10.83. HRMS (ESI-ion trap) m/z: calculated for C13H20N5O2, [M + H]+ 278.1539; found, 278.1542. 3-(4-Amino-3-azidophenyl)-3-ethylpiperidine-2,6-dione (2y). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:35) to afford 2y (82 mg, 60%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 6.90 (d, J = 1.9 Hz, 1H), 6.83 (dd, J = 8.3, 1.9 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 3.86 (s, 2H), 2.59 (dd, J = 10.6, 7.2 Hz, 1H), 2.49−2.41 (m, 1H), 2.34−2.28 (m, 1H), 2.19 (td, J = 13.9, 4.5 Hz, 1H), 2.05−1.98 (m, 1H), 1.88 (dq, J = 14.6, 7.4 Hz, 1H), 0.86 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 175.52, 172.44, 145.72, 128.17, 127.15, 115.42, 50.33, 32.96, 29.35, 27.04, 9.00. HRMS (ESI-ion trap) m/z: calculated for C13H16N5O2, [M + H]+ 274.1226; found, 274.1230. 11216

DOI: 10.1021/acs.joc.7b01594 J. Org. Chem. 2017, 82, 11212−11217

Note

The Journal of Organic Chemistry 2-Iodo-6-methylaniline (3a).19 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 3a (64 mg, 55%) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 3.63 (s, 2H), 2.13 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 144.35, 138.66, 135.57, 124.94, 116.88, 79.52, 17.02. 2-Bromo-6-methylaniline (4a). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 4a (42 mg, 45%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 7.02 (d, J = 7.5 Hz, 1H), 6.69 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 3.53 (s, 2H), 2.13 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 144.68, 130.53, 127.05, 122.39, 118.68, 115.01, 17.41. HRMS (ESI-ion trap) m/z: calculated for C7H9BrN, [M + H]+ 185.9840; found, 185.9835. Ethyl 4-Amino-3-iodobenzoate (3b).19 The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:50) to afford 3b (57 mg, 39%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 15.9 Hz, 2H), 8.05 (s, 1H), 4.99 (s, 2H), 4.3 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 164.52, 145.70, 133.33, 121.31, 107.41, 61.09, 14.38. Ethyl 4-Amino-3-bromobenzoate (4b). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:30) to afford 4b (33 mg, 27%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 15.9 Hz, 2H), 8.06 (s, 1H), 4.99 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 164.51, 145.66, 133.34, 121.30, 107.39, 61.07, 14.36. HRMS (ESI-ion trap) m/z: calculated for C9H11BrNO2, [M + H]+ 243.9895; found, 243.9889. 6-(1-(2-Amino-5-(3-ethyl-2,6-dioxopiperidin-3-yl)phenyl)-1H1,2,3-triazol-4-yl)-2-butyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (5). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:50) to afford 5 (89 mg, 81%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 8.55 (s, 1H), 8.05 (d, J = 12.3 Hz, 2H), 7.45−7.40 (m, 2H), 7.29 (s, 1H), 7.17−7.13 (m, 2H), 6.81 (d, J = 8.6 Hz, 1H), 4.73 (s, 2H), 3.80−3.78 (m, 2H), 2.57 (dd, J = 14.2, 3.5 Hz, 1H), 2.48−2.40 (m, 2H), 2.33−2.25 (m, 3H), 2.15 (m, J = 14.1, 4.5 Hz, 2H), 1.97 (dd, J = 14.2, 7.3 Hz, 1H), 1.86 (dd, J = 14.2, 7.3 Hz, 1H), 1.27−1.20 (m, 3H), 0.81 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 177.5, 167.2, 167.1, 165.9, 164.9, 156.4, 154.9, 154.5, 134.5, 131.1, 130.0, 129.7, 129.1, 129.1, 126.8, 113.6, 112.4, 95.3, 79.4, 72.2, 70.5, 47.87, 47.0, 44.7, 41.5, 20.7, 11.7. HRMS (ESI-ion trap) m/z: calculated for C31H31N6O4, [M + H]+ 551.2329; found, 551.2336.

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Zhejiang Province (2014C33141), and Project of Department of Science Technology Jinhua City (2013-3-003) for financial support.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01594. Copies of spectra (PDF)

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REFERENCES

(1) (a) Zhu, W.; Ma, D. Chem. Commun. 2004, 888−889. (b) Azad, C. S.; Narula, A. K. RSC Adv. 2015, 5, 100223−100227. (c) Xie, F.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2013, 52, 11862−11866. (d) Rabet, P. T. G.; Fumagalli, G.; Boyd, S.; Greaney, M. F. Org. Lett. 2016, 18, 1646−1649. (e) Goswami, M.; de Bruin, B. Eur. J. Org. Chem. 2017, 2017, 1152−1176. (2) (a) Du, B. N.; Jiang, X. Q.; Sun, P. P. J. Org. Chem. 2013, 78, 2786−2791. (b) Chu, L. L.; Yue, X. Y. Org. Lett. 2010, 12, 1644−1647. (3) Wang, C.; Ikhlef, D.; Kahlal, S.; Saillard, J. Y.; Astruc, D. Coord. Chem. Rev. 2016, 316, 1−20. (4) Zhou, S. G.; Liao, H. M.; Liu, M. M.; Feng, G. B.; Fu, B. L.; Li, R. J.; Cheng, M. S.; Zhao, Y. F.; Gong, P. Bioorg. Med. Chem. 2014, 22, 6438−6452. (5) Tang, C.; Jiao, N. J. Am. Chem. Soc. 2012, 134, 18924−18927. (6) (a) Xu, J.; Shen, C.; Zhu, X. L.; Zhang, P. F.; Ajitha, M. J.; Huang, K. W.; An, Z. F.; Liu, X. G. Chem. - Asian J. 2016, 11, 882−892. (b) Lubriks, D.; Sokolovs, I.; Suna, E. J. Am. Chem. Soc. 2012, 134, 15436−15442. (7) Li, G.; Liu, Y.; Yu, X. R.; Li, X. Y. Bioconjugate Chem. 2014, 25, 1172−1180. (8) Fan, Y. P.; Wan, W.; Ma, G. B.; Gao, W.; Jiang, H. Z.; Zhu, S. Z.; Hao, J. Chem. Commun. 2014, 50, 5733−5736. (9) Dou, Y. D.; Xie, Z. D.; Sun, Z. G.; Fang, F. L.; Shen, C.; Zhang, P. F.; Zhu, Q. ChemCatChem 2016, 8, 3570−3574. (10) (a) Truce, W.; Goralski, C.; Christensen, L.; Bavry, R. J. Org. Chem. 1970, 35, 4217−4220. (b) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128, 6790−6791. (11) Liu, W.; Groves, J. T. Acc. Chem. Res. 2015, 48, 1727−1735. (12) (a) Severino, F.; Brito, J. L.; Laine, J.; Fierro, J. L. G.; Agudo, A. L. J. Catal. 1998, 177, 82−95. (b) Liu, P.; Hensen, E. J. M. J. Am. Chem. Soc. 2013, 135, 14032−14035. (13) (a) Deutsch, K. L.; Shanks, B. H. J. Catal. 2012, 285, 235−241. (b) Mondal, R. R.; Khamarui, S.; Maiti, D. K. ACS Omega. 2016, 1, 251−263. (14) Platzman, I.; Brener, R.; Haick, H.; Tannenbaum, R. J. Phys. Chem. C 2008, 112, 1101−1108. (15) (a) Li, J. M.; Wang, Y. H.; Yu, Y.; Wu, R. B.; Weng, J.; Lu, G. ACS Catal. 2017, 7, 2661−2667. (b) Shang, M.; Sun, S. Z.; Dai, H. X.; Yu, J. Q. Org. Lett. 2014, 16, 5666−5669. (16) Li, D. K.; Mao, T. T.; Huang, J. B.; Zhu, Q. Chem. Commun. 2017, 53, 1305−1308. (17) Barlow, T. M. A.; Jian, M.; Guillemyn, K.; Tourwé, D.; Caveliers, V.; Ballet, S. Org. Biomol. Chem. 2016, 14, 4669−4677. (18) Shen, M. H.; Driver, T. G. Org. Lett. 2008, 10, 3367−3370. (19) Ikeda, A.; Omote, M.; Kusumoto, K.; Komori, M.; Tarui, A.; Sato, K.; Ando, A. Org. Biomol. Chem. 2016, 14, 2127−2133.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yuguo Zheng: 0000-0002-6358-6243 Qing Zhu: 0000-0002-0761-9434 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the National Natural Science Foundation of China (Nos. 21472172, 21272212, and 21572190), Natural Science Foundation of Zhejiang Province (No. LY17B060009), Project of Science Technology Department of 11217

DOI: 10.1021/acs.joc.7b01594 J. Org. Chem. 2017, 82, 11212−11217