Next Article in Journal
Chlorine Isotope Effects from Isotope Ratio Mass Spectrometry Suggest Intramolecular C-Cl Bond Competition in Trichloroethene (TCE) Reductive Dehalogenation
Next Article in Special Issue
Palladium Catalyzed Heck Arylation of 2,3-Dihydrofuran—Effect of the Palladium Precursor
Previous Article in Journal
Antiprotozoal Activity of Achillea ptarmica (Asteraceae) and Its Main Alkamide Constituents
Previous Article in Special Issue
Repetitive Two-Step Method for o,o,p- and o,p-Oligophenylene Synthesis through Pd-Catalyzed Cross-Coupling of Hydroxyterphenylboronic Acid
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 19
Issue 5
10.3390/molecules19056439
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Palladium-Catalyzed Direct Addition of 2-Aminobenzonitriles to Sodium Arylsulfinates: Synthesis of o-Aminobenzophenones

by
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
2
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035, China
*
Author to whom correspondence should be addressed.
Molecules 2014, 19(5), 6439-6449; https://doi.org/10.3390/molecules19056439
Submission received: 3 May 2014 / Revised: 15 May 2014 / Accepted: 19 May 2014 / Published: 20 May 2014
(This article belongs to the Special Issue Palladium Catalysts)
Browse Figures
Versions Notes

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.

Graphical Abstract

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 550
Scheme 1. Pd-catalyzed addition of arylsulfinates to 2-aminobenzonitriles.
Scheme 1. Pd-catalyzed addition of arylsulfinates to 2-aminobenzonitriles.
Molecules 19 06439 g001

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
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 2a–h 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 3e–g (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
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 (1a–h) 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 550
Scheme 2. Substrate scope of 2-aminobenzonitriles a.
Scheme 2. Substrate scope of 2-aminobenzonitriles a.
Molecules 19 06439 g002
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 550
Scheme 3. Proposed mechanism.
Scheme 3. Proposed mechanism.
Molecules 19 06439 g003

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: https://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.

References

  1. Singh, R.K.; Prasad, D.N.; Bhardwaj, T.R. Design, synthesis and evaluation of aminobenzophenone derivatives containing nitrogen mustard moiety as potential central nervous system antitumor agent. Med. Chem. Res. 2013, 22, 5901–5911. [Google Scholar] [CrossRef]
  2. Liou, J.-P.; Chang, C.-W.; Song, J.-S.; Yang, Y.-N.; Yeh, C.-F.; Tseng, H.-Y.; Lo, Y.-K.; Chang, Y.-L.; Chang, C.-M.; Hsieh, H.-P. Synthesis and structure activity relationship of 2-aminobenzophenone derivatives as antimitotic agents. J. Med. Chem. 2002, 45, 2556–2562. [Google Scholar] [CrossRef]
  3. Castellano, S.; Taliani, S.; Viviano, M.; Milite, C.; da Pozzo, E.; Costa, B.; Barresi, E.; Bruno, A.; Cosconati, S.; Marinelli, L.; et al. Structure–activity relationship refinement and further assessment of 4-phenylquinazoline-2-carboxamide translocator protein ligands as antiproliferative agents in human glioblastoma tumors. J. Med. Chem. 2014, 57, 2413–2428. [Google Scholar] [CrossRef]
  4. Kobayashi, K.; Fujita, S.; Fukamachi, S.; Konishi, H. One-pot synthesis of quinoline-2(1H)-thiones from 2-isocyanostyrenes via electrocyclic reaction of the corresponding 2-isothiocyanatestyrenes. Synthesis 2009, 2009, 3378–3382. [Google Scholar] [CrossRef]
  5. Cai, S.; Zeng, J.; Bai, Y.; Liu, X. Access to Quinolines through gold-catalyzed intermolecular cycloaddition of 2-aminoaryl carbonyls and internal alkynes. J. Org. Chem. 2012, 77, 801–807. [Google Scholar] [CrossRef]
  6. Yan, Y.; Wang, Z. Metal-free intramolecular oxidative decarboxylative amination of primary a-amino acids with product selectivity. Chem. Commun. 2011, 47, 9513–9515. [Google Scholar] [CrossRef]
  7. Anand, N.; Reddy, K.H.P.; Satyanarayana, T.; Rao, K.S.R.; Burri, D.R. A magnetically recoverable γ-Fe2O3 nanocatalyst for the synthesis of 2-phenylquinazolines under solvent-free conditions. Catal. Sci. Technol. 2012, 2, 570–574. [Google Scholar] [CrossRef]
  8. Ren, L.; Lei, T.; Ye, J.; Gong, L. Step-economical synthesis of tetrahydroquinolines by asymmetric relay catalytic Friedläender condensation/transfer hydrogenation. Angew. Chem. Int. Ed. Engl. 2012, 51, 771–774. [Google Scholar] [CrossRef]
  9. Earmme, T.; Ahmed, E.; Jenekhe, S.A. Solution-processed highly efficient blue phosphorescent polymer light-emitting diodes enabled by a new electron transport material. Adv. Mater. 2010, 22, 4744–4748. [Google Scholar] [CrossRef]
  10. Walsh, D.A. The Synthesis of 2-aminobenzophenones. Synthesis 1980, 1980, 677–688. [Google Scholar] [CrossRef]
  11. Xie, Y.; Yang, Y.; Huang, L.; Zhang, X.; Zhang, Y. Pd-Catalyzed arylation/oxidation of benzylic C-H bond. Org. Lett. 2012, 14, 1238–1241. [Google Scholar]
  12. Khedkar, M.V.; Tambade, P.J.; Qureshi, Z.S.; Bhanage, B.M. Pd/C: An efficient, heterogeneous and reusable catalyst for phosphane-free carbonylative suzuki coupling reactions of aryl and heteroaryl iodides. Eur. J. Org. Chem. 2010, 2010, 6981–6986. [Google Scholar]
  13. Cai, M.; Peng, J.; Hao, W.; Ding, G. A phosphine-free carbonylative cross-coupling reaction of aryl iodides with arylboronic acids catalyzed by immobilization of palladium in MCM-41. Green Chem. 2011, 13, 190–196. [Google Scholar] [CrossRef]
  14. Mizuno, M.; Yamano, M. A new practical one-pot conversion of phenols to anilines. Org. Lett. 2005, 7, 3629–3631. [Google Scholar] [CrossRef]
  15. Thakur, K.G.; Ganapathy, D.; Sekar, G. d-Glucosamine as a green ligand for copper catalyzed synthesis of primary aryl amines from aryl halides and ammonia. Chem. Commun. 2011, 47, 5076–5078. [Google Scholar] [CrossRef]
  16. Mateos, C.; Rincón, J.A.; Villanueva, J. Efficient and scalable synthesis of ketones via nucleophilic Grignard addition to nitriles using continuous flow chemistry. Tetrahedron Lett. 2013, 45, 2226–2230. [Google Scholar]
  17. Zhou, X.; Luo, J.; Liu, J.; Peng, S.; Deng, D. Pd-catalyzed desulfitative heck coupling with dioxygen as the terminal oxidant. Org. Lett. 2011, 13, 1432–1436. [Google Scholar]
  18. Rao, H.; Yang, L.; Shuai, Q.; Li, C. Rhodium-catalyzed aerobic coupling between aldehydes and arenesulfinic acid salts: A novel synthesis of aryl ketones. Adv. Synth. Catal. 2011, 353, 1701–1706. [Google Scholar] [CrossRef]
  19. Chen, J.; Sun, Y.; Liu, B.; Liu, D.; Cheng, J. The palladium-catalyzed desulfitative cyanation of arenesulfonyl chlorides and sodium sulfinates. Chem. Commun. 2012, 48, 449–451. [Google Scholar]
  20. Liu, B.; Guo, Q.; Cheng, Y.; Lan, J.; You, J. Palladium-catalyzed desulfitative C-H arylation of heteroarenes with sodium sulfinates. Chem. Eur. J. 2011, 17, 13415–13419. [Google Scholar] [CrossRef]
  21. Zhao, F.; Tan, Q.; Xiao, F.; Zhang, S.; Deng, G. Palladium-catalyzed desulfitative cross-coupling reaction of sodium sulfinates with benzyl chlorides. Org. Lett. 2013, 15, 1520–1523. [Google Scholar] [CrossRef]
  22. Fleming, F.F.; Wang, Q. Unsaturated nitriles: Conjugate additions of carbon nucleophiles to a recalcitrant class of acceptors. Chem. Rev. 2003, 103, 2035–2078. [Google Scholar] [CrossRef]
  23. Kukushkin, V.Y.; Pombeiro, A.J.L. Additions to metal-activated organonitriles. Chem. Rev. 2002, 102, 1771–1802. [Google Scholar] [CrossRef]
  24. Rach, S.F.; Kuhn, F.E. Nitrile ligated transition metal complexes with weakly coordinating counteranions and their catalytic applications. Chem. Rev. 2009, 109, 2061–2080. [Google Scholar] [CrossRef]
  25. Larock, R.C.; Tian, Q.; Pletnv, A.A. Carbocycle synthesis via carbopalladation of nitriles. J. Am. Chem. Soc. 1999, 121, 3238–3239. [Google Scholar] [CrossRef]
  26. Ueura, K.; Satoh, T.; Miura, M. Rhodium-catalyzed arylation using arylboron compounds: Efficient coupling with aryl halides and unexpected multiple arylation of benzonitrile. Org. Lett. 2005, 7, 2229–2231. [Google Scholar] [CrossRef]
  27. Wong, Y.-C.; Parthasarathy, K.; Cheng, C.-H. Direct synthesis of arylketones by nickel-catalyzed addition of arylboronic acids to nitriles. Org. Lett. 2010, 12, 1736–1739. [Google Scholar] [CrossRef]
  28. Tsui, G.C.; Glenadel, Q.; Lau, C.; Lautens, M. Rhodium(I)-catalyzed addition of arylboronic acids to (benzyl-/arylsulfonyl)acetonitriles: Efficient synthesis of (Z)-β-sulfonylvinylamines and β-keto sulfones. Org. Lett. 2011, 13, 208–211. [Google Scholar] [CrossRef]
  29. Lindh, J.; Sjöberg, P.J.R.; Larhed, M. Synthesis of aryl ketones by palladium(II)-catalyzed decarboxylative addition of benzoic acids to nitriles. Angew. Chem. Int. Ed. Engl. 2010, 49, 7733–7737. [Google Scholar]
  30. Hsieh, J.-C.; Chen, Y.-C.; Cheng, A.; Tseng, H.-C. Nickel-catalyzed intermolecular insertion of aryl iodides to nitriles: A novel method to synthesize arylketones. Org. Lett. 2012, 14, 1282–1285. [Google Scholar]
  31. Wang, X.; Liu, M.; Xu, L.; Wang, Q.; Chen, J.; Ding, J.; Wu, H. Palladium-catalyzed addition of potassium aryltrifluoroborates to aliphatic nitriles: Synthesis of alkyl aryl ketones, diketone compounds, and 2-arylbenzo[b]furans. J. Org. Chem. 2013, 78, 5273–5281. [Google Scholar] [CrossRef]
  32. Wang, X.; Wang, X.; Liu, M.; Ding, J.; Chen, J.; Wu, H. Palladium-catalyzed reaction of arylboronic acids with aliphatic nitriles: Synthesis of alkyl aryl ketones and 2-aryl benzofurans. Synthesis 2013, 45, 2241–2244. [Google Scholar] [CrossRef]
  33. Zheng, H.; Zhang, Q.; Chen, J.; Liu, M.; Cheng, S.; Ding, J.; Wu, H.; Su, W. Copper(II) acetate-catalyzed addition of arylboronic acids to aromatic aldehydes. J. Org. Chem. 2009, 74, 943–945. [Google Scholar]
  34. Qin, C.; Wu, H.; Chen, J.; Liu, M.; Cheng, J.; Su, W.; Ding, J. Palladium-catalyzed aromatic esterification of aldehydes with organoboronic acids and molecular oxygen. Org. Lett. 2008, 10, 1537–1540. [Google Scholar]
  35. Qin, C.; Wu, H.; Cheng, J.; Chen, X.; Liu, M.; Zhang, W.; Su, W.; Ding, J. The palladium-catalyzed addition of aryl- and heteroarylboronic acids to aldehydes. J. Org. Chem. 2007, 72, 4102–4107. [Google Scholar]
  36. Zheng, H.; Ding, J.; Chen, J.; Liu, M.; Gao, W.; Wu, H. Copper-catalyzed arylation of arylboronic acids with aldehydes. Synlett 2011, 2011, 1626–1630. [Google Scholar] [CrossRef]
  37. Qin, C.; Chen, J.; Wu, H.; Cheng, J.; Zhang, Q.; Zuo, B.; Su, W.; Ding, J. One-pot synthesis of diaryl ketones from aldehydes via palladium-catalyzed reaction with aryl boronic acids. Tetrahedron Lett. 2008, 49, 1884–1888. [Google Scholar] [CrossRef]
  38. Lothrop, W.C.; Goodwin, P.A. New modification of the Ullmann synthesis of fluorene derivatives. J. Am. Chem. Soc. 1943, 65, 363–367. [Google Scholar] [CrossRef]
  39. Martinez-Viturro, C.M.; Dominguez, D. Synthesis of aza analogues of the anticancer agent batracylin. Tetrahedron Lett. 2007, 48, 4707–4710. [Google Scholar] [CrossRef]
  • Sample Availability: Not available.

Share and Cite

MDPI and ACS Style

Chen, J.; Li, J.; Su, W. Palladium-Catalyzed Direct Addition of 2-Aminobenzonitriles to Sodium Arylsulfinates: Synthesis of o-Aminobenzophenones. Molecules 2014, 19, 6439-6449. https://doi.org/10.3390/molecules19056439

AMA Style

Chen J, Li J, Su W. Palladium-Catalyzed Direct Addition of 2-Aminobenzonitriles to Sodium Arylsulfinates: Synthesis of o-Aminobenzophenones. Molecules. 2014; 19(5):6439-6449. https://doi.org/10.3390/molecules19056439

Chicago/Turabian Style

Chen, Jiuxi, Jianjun Li, and Weike Su. 2014. "Palladium-Catalyzed Direct Addition of 2-Aminobenzonitriles to Sodium Arylsulfinates: Synthesis of o-Aminobenzophenones" Molecules 19, no. 5: 6439-6449. https://doi.org/10.3390/molecules19056439

Article Metrics

Back to TopTop