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Molecules 2014, 19(5), 6439-6449; doi:10.3390/molecules19056439

Article
Palladium-Catalyzed Direct Addition of 2-Aminobenzonitriles to Sodium Arylsulfinates: Synthesis of o-Aminobenzophenones
Jiuxi Chen 1,2, Jianjun Li 1 and Weike Su 1,*
1
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China; E-Mails: jiuxichen@163.com (C.J.); lijjun@126.com (J.L.)
2
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035, China
*
Author to whom correspondence should be addressed; E-Mail: pharmlab@zjut.edu.cn; Tel./Fax: +86-571-8882-0899.
Received: 3 May 2014; in revised form: 15 May 2014 / Accepted: 19 May 2014 /
Published: 20 May 2014

Abstract

: The first example of the palladium-catalyzed synthesis of o-aminobenzophenones in moderate to excellent yields via a direct addition of sodium arylsulfinates to unprotected 2-aminobenzonitriles was reported. A plausible mechanism for the formation of o-aminobenzophenones involving desulfination and addition reactions was proposed. The utility of this transformation was demonstrated by its compatibility with a wide range of functional groups. Thus, the method represents a convenient and practical strategy for synthesis of o-aminobenzophenones.
Keywords:
palladium; 2-aminobenzonitriles; arylsulfinates; o-aminobenzophenones

1. Introduction

o-Aminobenzophenones have drawn much attention due to their various pharmaceutical activities in medicine chemistry [1,2,3], their use as versatile intermediates for further transformations in synthetic chemistry [4,5,6,7,8] and their application in materials chemistry [9]. As a consequence, wide demands for diverse o-aminobenzophenones in various fields have promoted the development of practical and diversified synthetic methods [10,11,12,13,14,15]. Recently, Mateos reported the addition reaction of Grignard reagents to 2-aminobenzonitrile for the construction of o-aminobenzophenone using continuous flow chemistry [16]; however, the rigorous conditions have restricted its application and substrate diversity. Compared with Grignard reagents, sodium arylsulfinates are relatively stable, easy to handle, and are generally used as the aryl source in transition-metal-catalyzed desulfinative reactions [17,18,19,20,21]. On the other hand, transformations of nitriles play an important role in both the laboratory and industry due to their well-recognized chemical versatility [22,23]. However, the nitrile group is generally inert in organometallic reactions, and thus acetonitrile or benzonitrile usually participate as solvents or ligands [24] in metal-catalyzed reactions. The Larock group [25] pioneered the addition of arylpalladium species to the cyano group. Since then, transition metal-catalyzed addition reactions of arylation reagents to nitriles have been developed [26,27,28,29,30]. Recently, we reported the palladium-catalyzed addition of organoboron reagents to aliphatic nitriles for the preparation of alkyl aryl ketones, diketone compounds, and 2-arylbenzo[b]furans [31,32]. However, there is a major limitation in that trace or low yields of the desired products were observed when the substrates bore a free amino group; therefore developing a new catalyst system that would allow for the efficient reaction of problematic substrate combinations is highly desirable. These reasons may be due to side reactions and catalyst deactivation in the presence of the free amino group. In addition, nitriles bearing an electron-donating amino group, are less electrophilic, and hence addition of arylpalladium species to the cyano group ocurrs more slowly than with their electron-neutral analogues. We envisioned that electrophiles might exhibit greatly enhanced reactivity due to the formation of stable, weak coordinating and electron withdrawing cationic species by adding an appropriate additive to the reaction system.

To the best of our knowledge, examples of o-aminobenzophenone synthesis using sodium arylsulfinates as coupling partners have never been reported. As part of the continuing efforts in our laboratory toward the development of palladium-catalyzed addition reactions [31,32,33,34,35,36,37], herein we report a simple and efficient protocol for the synthesis of o-aminobenzophenones by palladium-catalyzed direct addition of sodium arylsulfinates to unprotected 2-aminobenzonitriles (Scheme 1).

Molecules 19 06439 g001 1024
Scheme 1. Pd-catalyzed addition of arylsulfinates to 2-aminobenzonitriles.

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Scheme 1. Pd-catalyzed addition of arylsulfinates to 2-aminobenzonitriles.
Molecules 19 06439 g001 1024

2. Results and Discussion

We began our study by examining the reaction between 2-aminobenzonitrile (1a) and sodium benzenesulfinate (2a) to establish the optimal reaction conditions (Table 1). On the basis of our previous addition protocol of organoborons to nitriles [31] a test reaction with Pd(O2CCF3)2 and 2,2'-bipyridine (bpy) as the catalytic system was performed under an air atmosphere. To our delight, the desired product o-aminobenzophenone (3a) was isolated in 18% yield (Table 1, entry 1). Encouraged by this promising result, a series of trial experiments were performed in the presence of palladium catalysts and with adjustments to the reaction parameters in order to obtain more satisfactory results. First, we investigated different palladium catalysts. Among the palladium sources used, Pd(OAc)2 exhibited the highest catalytic reactivity, with 32% yield (Table 1, entries 1–6). Subsequently, various additives were examined in this transformation. Screening revealed that the use of p-nitrobenzene-sulfonic acid (p-NBSA) as the additive that achieved the best result (73% yield, Table 1, entry 11). Other additives, including CF3CO2H, CH3CO2H, CH3SO3H, PhSO3H and p-toluenesulfonic acid (p-TSA), were less efficient (Table 1, entries 1, 7–10). We next examined the solvent effect and found that THF or 2-MeTHF were superior to dioxane, toluene, and DMF (Table 1, entries 11–15). We were pleased to discover that only when the model reaction was performed in THF under a N2 atmosphere did the yield dramatically increase to 91% yield (Table 1, entry 16).

Table Table 1. Optimization of the reaction conditions a. Molecules 19 06439 i001

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Table 1. Optimization of the reaction conditions a. Molecules 19 06439 i001
EntryPd sourceAdditiveSolventYield (%) b
1Pd(CF3CO2)2CF3CO2HTHF18
2PdCl2CF3CO2HTHF11
3Pd(OAc)2CF3CO2HTHF32
4Pd(acac)2CF3CO2HTHF13
5Pd(PPh3)4CF3CO2HTHFtrace
6PdCl2(dppe)CF3CO2HTHF0
7Pd(OAc)2CH3CO2HTHF10
8Pd(OAc)2CH3SO3HTHF44
9Pd(OAc)2PhSO3HTHF59
10Pd(OAc)2p-TSA cTHF61
11Pd(OAc)2p-NBSA dTHF73
12Pd(OAc)2p-NBSAtoluene42
13Pd(OAc)2p-NBSA2-MeTHF69
14Pd(OAc)2p-NBSAdioxane53
15Pd(OAc)2p-NBSADMFtrace
16Pd(OAc)2p-NBSATHF91 e

a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), indicated Pd source (10 mol%), bpy (20 mol%), additive (3 mmol), solvent (2 mL), H2O (1 mL), 80 °C, 48 h, air; b Isolated yield; c p-TSA = p-toluenesulfonic acid; d p-NBSA = p-nitrobenzenesulfonic acid; e Under a N2 atmosphere.

With the optimized reaction conditions in hand, we next explored the substrate scope of the addition reaction of 2-aminobenzonitriles 1 with sodium arylsulfinates 2 as shown in Scheme 1.

First, the addition reaction of 2-aminobenzonitrile (1a) with various sodium arylsulfinates 2ah was investigated under our standard conditions (Table 2). The mono-substituent positions of the phenyl moiety of sodium arylsulfinates were evaluated, and the results demonstrated that steric effects of substituents had an obvious impact on the yield of the reaction. For example, the addition reaction of 1a with para- and ortho-tolylsulfinate (2b and 2c) provided 87% of 3b, while the yield of 3cdecreased to 64% (Table 2, entries 2–3). The electronic properties of the substituents on the phenyl ring of the sodium arylsulfinates also affected the yields of the reaction to some extent. In general, the sodium arylsulfinates bearing an electron-donating substituent (e.g., −Me and −OMe) produced slightly higher yields than those analogues bearing an electron-withdrawing substituent (e.g., −F, −Cl and −Br) (Table 2, entries 2, 4–7). Substrate 2h, bearing a naphthyl group, was treated with 1a to deliver the desired product 3h in 90% yield (Table 2, entry 8). It is noteworthy that the fluoro, chloro, and bromo moieties (commonly used for cross-coupling reactions) in substrates were all tolerated and afforded several halogen-containing products 3eg (Table 2, entries 5–7) in acceptable yields, leading to a useful handle for further cross-coupling reactions. However, treatment of an alkylsulfinate such as sodium methanesulfinate with 1a under the optimized conditions afforded only a trace amount of the desired product.

Table Table 2. Substrate scope of sodium arylsulfinates a. Molecules 19 06439 i002

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Table 2. Substrate scope of sodium arylsulfinates a. Molecules 19 06439 i002
EntryArSO2Na (2)Product (3)Yield (%) b
1 Molecules 19 06439 i0033a91
2 Molecules 19 06439 i0043b88
3 Molecules 19 06439 i0053c64
4 Molecules 19 06439 i0063d85
5 Molecules 19 06439 i0073e81
6 Molecules 19 06439 i0083f83
7 Molecules 19 06439 i0093g80
8 Molecules 19 06439 i0103h90

a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), Pd(OAc)2 (10 mol%), bpy (20 mol%), p-NBSA (3 mmol), THF (2 mL), H2O (1 mL), 80 °C, 48 h, N2; b Isolated yield.

Next, we turned our attention to the effect of the reactions of sodium benzenesulfinate (2a) with various 2-aminobenzonitriles (1ah) under our standard conditions and the results are summarized in Scheme 2. As expected, the groups on the phenyl ring of 2-aminobenzonitriles, such as methyl, methoxy, fluoro, chloro, bromo, and nitro were quite compatible. The electronic properties of the groups on the phenyl ring moiety of 2-aminobenzonitriles had little effect on the reaction. For example, substrates 1b and 1c bearing an electron-donating substituent (e.g., −Me or −OMe), reacted with 2a smoothly and afforded the corresponding products 3i and 3j in 93% and 90% yields, respectively (Scheme 2, entries 2–3). Substrates 1d, 1e, 1f and 1g bearing an electron-withdrawing substituent (e.g., −F, −Cl, −Br and −NO2) were treated with 2a to afford 89%, 92%, 90% and 96% yields of 3k, 3l, 3m and 3n, respectively (Scheme 2, entries 4–7). Gratifyingly, the substrate 2-aminonicotinonitrile (1h), bearing a heteroaryl group underwent the reaction smoothly to afford the corresponding product 3o in 83% yield (Scheme 2, entry 8).

Molecules 19 06439 g002 1024
Scheme 2. Substrate scope of 2-aminobenzonitriles a.

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Scheme 2. Substrate scope of 2-aminobenzonitriles a.
Molecules 19 06439 g002 1024

a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), Pd(OAc)2 (10 mol%), bpy (20 mol%), p-NBSA (3 mmol), THF (2 mL), H2O (1 mL), 80 °C, 48 h, N2; Isolated yield was given in parenthesis.

A plausible mechanism for the formation of o-aminobenzophenones is proposed in Scheme 3. The following key steps are included in the catalytic pathway: (i) coordination of Pd(OAc)2 with arylsulfinic acids (or sodium arylsulfinates) to afford a palladium species A; (ii) the desulfination of the arylsulfinic acid to give aryl-palladium species B; (iii) the formation of intermediate D by the coordination of species B with cyano group in 2-cyanobenzenaminium (C); (iv) carbopalladation of the 2-aminobenzonitriles to produce the corresponding ketimine complex E; (v) protonation of the ketimine complex E to afford the ketimine intermediate F and regenerate an active palladium species. Hydrolysis of the ketimine intermediate F delivers the corresponding o-aminobenzophenones as the desired products.

Molecules 19 06439 g003 1024
Scheme 3. Proposed mechanism.

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Scheme 3. Proposed mechanism.
Molecules 19 06439 g003 1024

3. Experimental

General Information

Melting points are uncorrected. 1H-NMR and 13C-NMR spectra were measured on a 500 MHz spectrometer using CDCl3 as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts are given n δ relative to TMS, and the coupling constants J are given in hertz. Other commercially obtained reagents were used without further purification. All reactions under N2atmosphere were conducted using standard Schlenk techniques. Column chromatography was performed using EM silica gel 60 (300–400 mesh).

General Procedure for the Synthesis of o-Aminobenzophenones

Under a N2 atmosphere, a Schlenk tube was charged with 2-aminobenzonitrile 1 (0.3 mmol), sodium arylsulfinate 2 (0.6 mmol), Pd(OAc)2 (10 mol %), bpy (20 mol %), p-NBSA (10 equiv), THF (2 mL), and H2O (1 mL) at room temperature. The reaction mixture was stirred vigorously at 80 °C for 48 h. The mixture was poured into ethyl acetate, which was washed with saturated NaHCO3 (2 × 10 mL) and then brine (1 × 10 mL). After the aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane/ethyl acetate) to afford the desired products 3.

2-Aminobenzophenone (3a). Pale yellow solid (91% yield), mp 110–112 °C (Lit. [13] 109–111 °C); 1H-NMR (CDCl3, 500 MHz): δ 7.63–7.64 (m, 2H), 7.31–7.54 (m, 4H), 7.26–7.28 (m, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.09 (s, 2H); 13C-NMR (CDCl3, 125 MHz) δ 199.1, 150.9, 140.1, 134.6, 134.2, 131.0, 129.1, 128.1, 118.2, 117.0, 115.5.

(2-Aminophenyl)(p-tolyl)methanone (3b) [5]. Pale yellow solid (88% yield), mp 92–93 °C (not reported); 1H-NMR (CDCl3, 500 MHz): δ 7.56 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.25–7.30 (m, 3H), 6.73 (d, J = 8.2 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 6.00 (s, 2H), 2.42 (s, 3H); 13C-NMR (CDCl3, 125 MHz) δ 198.8, 150.7, 141.7, 137.2, 134.4, 134.0, 129.4, 128.7, 118.6, 116.9, 115.5, 21.5.

(2-Aminophenyl)(o-tolyl)methanone (3c). Pale yellow solid (64% yield), mp 79–81 °C (Lit. [38] 84 °C); 1H-NMR (CDCl3, 500 MHz): δ 7.32–7.35 (m, 1H), 7.20–7.29 (m, 5H), 6.71 (d, J = 8.3 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 6.41 (s, 2H), 2.27 (s, 3H); 13C-NMR (CDCl3, 125 MHz) δ 200.8, 150.7, 140.1, 134.6, 134.3, 134.2, 130.0, 128.7, 126.6, 124.7, 117.9, 116.4, 115.1, 19.0.

(2-Aminophenyl)(4-methoxyphenyl)methanone (3d). Pale yellow solid (85% yield), mp 77–78 °C (Lit. [4] 75–76 °C); 1H-NMR (CDCl3, 500 MHz ): δ 7.68 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.62 (t, J = 7.1 Hz, 1H), 5.86 (s, 2H), 3.38 (s, 3H); 13C-NMR (CDCl3, 125 MHz) δ 197.8, 162.3, 150.4, 134.0, 133.7, 131.8, 122.2, 199.0, 117.0, 115.6, 113.4, 55.4.

(2-Aminophenyl)(4-fluorophenyl)methanone (3e) [6]. Pale yellow solid (81% yield), mp 128–129 °C (not reported); 1H-NMR (CDCl3, 500 MHz): δ 7.67–7.69 (m, 2H), 7.42 (d, J = 8.1 Hz, 1H), 7.29–7.32 (m, 1H), 7.14 (t, J = 8.7 Hz, 2H), 6.75 (d, J = 8.3 Hz, 1H), 6.62 (t, J = 7.6 Hz, 1H), 6.03 (s, 2H); 13C-NMR (CDCl3, 125 MHz) δ 197.5, 165.5, 163.5, 150.8, 136.1, 134.3, 134.2, 131.7, 131.6, 118.1, 117.1, 115.6, 115.3, 115.1.

(2-Aminophenyl)(4-chlorophenyl)methanone (3f) [5]. Pale yellow solid (83% yield), mp 100–101 °C (not reported); 1H-NMR (CDCl3, 500 MHz): δ 7.59 (d, J = 8.5 Hz, 2H), 7.31–7.44 (m, 3H), 7.26–7.28 (m, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.08 (s, 2H); 13C-NMR (CDCl3, 125 MHz) δ 197.9, 151.0, 138.4, 137.4, 134.5, 134.3, 130.6, 128.4, 117.9, 117.2, 115.7.

(2-Aminophenyl)(4-bromophenyl)methanone (3g) [5]. Pale yellow solid (80% yield), mp 109–111 °C (not reported); 1H-NMR (CDCl3, 500 MHz): δ 7.60 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.27–7.32 (m, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61 (t, J = 7.6 Hz, 1H), 6.10 (s, 2H); 13C-NMR (CDCl3, 125 MHz) δ 197.8, 151.0, 138.8, 134.5, 134.2, 131.4, 130.7, 125.8, 117.7, 117.1, 115.6.

(2-Aminophenyl)(naphthalen-2-yl)methanone (3h). Pale yellow solid (90% yield), mp 107–108 °C (Lit. [38] 106 °C); 1H-NMR (CDCl3, 500 MHz ): δ 8.12 (s, 1H), 7.89–7.93 (m, 3H), 7.77 (d, J = 8.5 Hz, 1H), 7.51–7.60 (m, 3H), 7.30–7.31 (m, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.62 (t, J = 7.1 Hz, 1H), 6.09 (s, 2H); 13C-NMR (CDCl3, 125 MHz) δ 199.0, 150.9, 137.3, 134.6, 134.6, 134.2, 132.3, 130.1, 129.1, 128.0, 127.8, 127.7, 126.7, 125.8, 118.5, 117.1, 115.6.

(2-Amino-4-methylphenyl)(phenyl)methanone (3i) [5]. Pale yellow solid (93% yield), mp 67–68 °C (not reported); 1H-NMR (CDCl3, 500 MHz ): δ 7.61 (d, J = 8.4 Hz, 2H), 7.44–7.52 (m, 3H), 7.33 (d, J = 8.2 Hz, 1H), 6.54 (s, 1H), 6.41 (d, J = 7.3 Hz, 1H), 6.12 (s, 2H), 2.29 (s, 3H); 13C-NMR (CDCl3, 125 MHz) δ 198.7, 151.3, 145.4, 140.5, 134.8, 130.8, 129.0, 128.1, 117.1, 117.0, 116.0, 21.8.

(2-Amino-4,5-dimethoxyphenyl)(phenyl)methanone (3j) [7]. Pale yellow solid (90% yield), mp 79–81 °C (not reported); 1H-NMR (CDCl3, 500 MHz): δ 7.61 (d, J = 8.4 Hz, 2H), 7.43–7.51 (m, 3H), 6.92 (s, 1H), 6.25 (s, 2H), 6.20 (s, 1H), 3.88 (s, 3H), 3.65 (s, 3H); 13C-NMR (CDCl3, 125 MHz) δ 197.2, 155.5, 148.6, 140.7, 139.7, 130.6, 128.7, 128.1, 116.7, 110.0, 99.3, 56.6, 55.9.

(2-Amino-5-fluorophenyl)(phenyl)methanone (3k) [8]. Pale yellow solid (89% yield), mp 117–118 °C (not reported); 1H-NMR (CDCl3, 500 MHz): δ 7.46–7.65 (m, 5H), 7.05–7.16 (m, 2H), 6.70–6.72 (m, 1H), 5.91 (s, 2H); 13C-NMR (CDCl3, 125 MHz) δ 198.0, 154.1, 152.2, 147.3, 139.4, 131.5, 129.1, 128.3, 122.3, 122.1, 119.1, 118.9, 118.2, 118.1, 117.9.

(2-Amino-5-chlorophenyl)(phenyl)methanone (3l) [5]. Pale yellow solid (92% yield), mp 97–98 °C (not reported); 1H-NMR (CDCl3, 500 MHz ): δ 7.63 (d, J = 8.4 Hz, 2H), 7.47–7.56 (m, 3H), 7.41 (d, J = 2.5 Hz, 1H), 7.23–7.25 (m, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.07 (s, 2H); 13C-NMR (CDCl3, 125 MHz) δ 198.0, 149.4, 139.3, 134.2, 133.3, 131.6, 129.1, 128.4, 120.0, 118.8, 118.5.

(2-Amino-5-bromophenyl)(phenyl)methanone (3m) [7]. Pale yellow solid (90% yield), mp 109–110 °C (not reported); 1H-NMR (CDCl3, 500 MHz): δ 7.63 (d, J = 8.4 Hz, 2H), 7.47–7.58 (m, 4H), 7.35–7.37 (m, 1H), 6.65 (d, J = 8.8 Hz, 1H), 6.10 (s, 2H); 13C-NMR (CDCl3, 125 MHz) δ 198.0, 149.8, 139.4, 136.9, 136.3, 131.7, 129.2, 128.5, 119.6, 118.9, 106.7.

(2-Amino-5-nitrophenyl)(phenyl)methanone (3n) [5]. Pale yellow solid (96% yield), mp 151–152 °C (not reported); 1H-NMR (CDCl3, 500 MHz ): δ 8.48 (s, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.51–7.66 (m, 5H), 6.90 (s, 2H), 6.76 (d, J = 9.2 Hz, 1H); 13C-NMR (CDCl3, 125 MHz) δ 198.0, 155.3, 138.5, 136.7, 132.2, 131.6, 129.3, 129.2, 128.7, 116.8, 116.1.

(2-Aminopyridin-3-yl)(phenyl)methanone (3o). Pale yellow solid (83% yield), mp 143–144 °C (Lit. [39] 140 °C); 1H-NMR (CDCl3, 500 MHz): δ 8.25 (d, J = 4.8 Hz, 2H), 7.76–7.77 (m, 1H), 7.48–7.62 (m, 5H), 6.82 (s, 2H), 6.59–6.62 (m, 1H); 13C-NMR (CDCl3, 125 MHz) δ 197.8, 159.8, 153.9, 143.0, 139.2, 131.6, 129.1, 128.4, 112.9, 112.1.

4. Conclusions

In summary, we have developed a new strategy for constructing o-aminobenzophenones in moderate to excellent yields via palladium-catalyzed direct addition reaction of sodium arylsulfinates to unprotected 2-aminobenzonitriles. Further efforts to extend this catalytic system to the preparation of other useful compounds are currently underway in our laboratories.

Supplementary Materials

Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/5/6439/s1.

Acknowledgments

We thank the National Natural Science Foundation of China (No. 21102105) and Zhejiang Provincial Natural Science Foundation (Nos. LY13B020015 and LY14B020009) for financial support.

Author Contributions

The contributions of the respective authors are as follows: Jiuxi Chen and Weike Su designed the experiments. Jiuxi Chen and Jianjun Li performed the experiments and developed the reactions. Jiuxi Chen had the idea for this work and prepared this manuscript with feedback from Jianjun Li and Weike Su.

Conflicts of Interest

The authors declare no conflict of interest.

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