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Communication

An Efficient Metal-Free Oxidative Esterification and Amination of Benzyl C–H Bond

by
Saiwen Liu
1,*,
Ru Chen
2,
Guowen He
1 and
Jin Zhang
1,*
1
College of Materials and Chemical Engineering, Hunan City University, Yiyang 413000, China
2
Yiyang Agriculture Products Quality Detect Center, Yiyang 413000, China
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(7), 1527; https://doi.org/10.3390/molecules25071527
Submission received: 25 February 2020 / Revised: 17 March 2020 / Accepted: 26 March 2020 / Published: 27 March 2020
(This article belongs to the Section Organic Chemistry)
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Abstract

:
An esterification and amination of benzylic C–H bonds was developed by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) under metal- and iodide-free conditions. Both carboxylic acids and amines could be used as ideal coupling partners for the oxidative coupling reactions with various diarylmethanes. A close to equal amount of coupling reagents was enough to afford the product in good to high yields.

Graphical Abstract

1. Introduction

Benzyl esters, which play a key role in many biologically active compounds, can be traditionally prepared by condensation of the corresponding benzyl alcohols with carboxylic acids in the presence of condensation reagents or their activated derivatives such as acyl chlorides in the presence of bases [1,2]. They also serve as the essential protecting groups in amino acids and their derivatives [3]. Therefore, development of efficient methods for rapid construction of benzyl esters has gained much attention and great progress has been made during the past several decades. Recently, the cleavage and functionalization of C–H bonds is of increasing interest for both academia and industry. Generally, the transformation mainly relies on transition metals [4,5,6]. This strategy has also been successfully employed for the direct esterification and amination of C–H bonds including benzylic C–H bonds under oxidative reaction conditions. Various transition-metals efficiently catalyzed the direct esterification [7,8] and amination [9,10,11] of C–H bonds. Due to the toxicity and cost of transition-metal catalysts, increasing interest has been paid on metal-free esterifications of benzylic C–H bonds.
Since Sinha and co-workers reported a 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) promoted acetoxylation of arylalkanes under sonochemical activation conditions in the absence of metal catalyst [12], various efficient esterification methods have been developed under metal-free conditions. The combination of quaternary ammonium iodides with strong oxidants was found to be an effective strategy for direct esterification and amination of benzylic C–H bonds [13,14,15,16]. Recently, Shen and co-workers reported the C–O coupling of C–H with carboxylic acids catalyzed by DDQ and tert-butyl nitrite using oxygen as the terminal oxidant [17]. However, large excess of carboxylic acids or amines are necessary to get satisfied reaction yields [18]. The development of esterification reactions using a near equal amount of reactants under metal-free conditions would be highly desirable. Herein, we report a DDQ promoted esterification and amination of diarylmethanes using only 1.5 equiv. of carboxylic acids and amines without the use of quaternary ammonium iodide or metal catalyst. The chloro-containing solvent plays an important role for this efficient transformation.

2. Results

2.1. Optimization of Reaction Conditions for Synthesis of Benzhydryl Benzoate 3a

We began our study by examining the reaction of diphenylmethane (1a) and with 1.5 equiv. of benzoic acid (2a) using DDQ as oxidant in 1,2-dichloroethane (DCE) at 100 °C under an atmosphere of argon. DDQ showed very good activity and the desired product benzhydryl benzoate (3a) was obtained in 95% yield as determined by GC (Table 1, entry 1). The oxidant played an important role for this kind of reaction. Other common oxidants, such as benzoquinone, peroxides and hydrogen peroxide, were ineffective and no desired product was observed (entries 2–6). Solvents also played an important role for the direct esterification. The reactions in chloro-containing solvents, such as chloroform, dichloromethane, and tetrachloroethane, all showed very good reactivity (entries 7–9). Other solvents, such as ethyl acetate, acetonitrile, and water, all decreased the reaction yields significantly (entries 10–13). Decreasing the reaction temperature decreased the reaction yield (entry 14). The reaction yields decreased when the reactions were carried out under oxygen and air (entries 15 and 16). Good yield still could be achieved when an equal amount of 2a was used (entry 17).

2.2. Substrate Scope for the Carboxylic Acids and Amines

With the optimized reaction conditions established, the scope of the reaction with respect to diphenylmethane (1a) and various carboxylic acids (2) was investigated (Table 2). The reactions with aromatic carboxylic acids bearing electron-donating groups and electron-withdrawing substituents at the para position proceeded smoothly to give the desired products in good yields (3b–3e). The position of the substituents on the phenyl ring of benzoic acids affected the reaction yield slightly, and the use of ortho-substituted benzoic acids also afforded the desired products in good yields. Under the optimized conditions, halogen substituents were all well tolerated (3e–3h). Good yield was obtained when 2-bromobenzoic acid was used, and the desired product 3h was achieved in 83% yield. More bulky substrates, such as 2,4,6-trimethylbenzoic acid, also efficiently reacted with 1a and gave the product in 85% yield (3j). Notably, high yield was achieved when hetero aromatic carboxylic acids, such as 3-methylthiophene-2-carboxylic acid, reacted with 1a, and the desired product 3k was obtained in 88% yield. To be our delight, aliphatic carboxylic acids, including formic acid, are also good coupling reagents for this kind of transformation, and the desired esters were formed in high yields (3m–3p). In addition to carboxylic acids, amines could also be used as ideal coupling partners for the oxidative coupling reaction. Diphenylmethane smoothly coupled with benzamide and gave the aminated product 4a in 62% yield. Moderate to good yields were obtained when sulfonamides were employed for the coupling reaction (4b–4d).

2.3. Substrate Scope for the Diarylmethanes

To further explore the scope of the reaction, various diarylmethanes (1) were employed to react with 2a under the optimized conditions (Table 3). A series of functional groups, including methyl, tert-butyl, fluoro, and chloro, were well tolerated under the optimized conditions (3t–3x). The position of the substituents on the phenyl ring of diphenylmethane only slightly affected the reaction yield (3q–3s). The desired product 3y was obtained in 40% yield when 1-benzyl-4-nitrobenzene was used. Unfortunately, this reaction condition was only suitable for diarylmethane substrates. Other benzylic substrates, such as toluene and ethylbenzene, were not reactive under the optimized reaction conditions.

2.4. Mechanism

To gather more information about the reaction mechanism, the radical scavenger 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) was added. No product was obtained from the reaction between diphenylmethane and benzoic acid with the influence of two equivalents of TEMPO (Scheme 1). This indicates that the present reaction process may involve radical intermediates.
A plausible mechanism to rationalize this transformation is illustrated in Scheme 2. The reaction of DDQ with diphenylmethane 1a generates a benzyl radical I and DDQH· via hydrogen atom transfer (HAT). The radicals continue to be transformed into the corresponding benzyl cation and DDQH anion via single electron transfer (SET) [17,18]. Finally, the benzoic acid 2a of the proton is abstracted by DDQH– and reacts with the cation II to obtain the desired product 3a and reduced hydroquinone DDQH2. However, the reason why the reaction only works well in chloro-containing solvents is not clear at this stage.

3. Materials and Methods

3.1. General Information

All experiments were carried out under an atmosphere of argon. Flash column chromatography was performed over silica gel 48–75 μm. 1H-NMR and 13C-NMR spectra were recorded on a Bruker-AV (400 and 100 MHz, respectively) instrument (Billerica, MA, USA) internally referenced to SiMe4 or chloroform signals. MS analyses were performed on an Agilent 5975 GC-MS instrument (EI) (Santa Clara, CA, USA). The new compounds were characterized by 1H NMR, 13C NMR, MS, and HRMS. The structure of known compounds were further corroborated by comparing their 1H-NMR, 13C-NMR, and MS data with those in the literature. All reagents were used as received from commercial sources without further purification. Diarylmethane derivatives 1 were synthesized based on relevant literatures [19].

3.2. General Procedure for the Synthesis of Benzhydryl Benzoate

An oven-dried pressure tube (10 mL) was charged with diphenylmethane (1a, 33.4 μL, 0.2 mmol), benzoic acid (2a, 36.6 mg, 0.3 mmol), DDQ (54.5 mg, 0.24 mmol), and DCE (0.6 mL). The reaction vessel was flushed with argon and sealed. The resulting solution was heated to 100 °C for 8 h. After cooling to room temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) to give 3a as white solid; yield: 46.1 mg (80%). (NMR spectra for all compounds shown in the Supplementary Materials).

3.3. Product Characterization

Benzhydryl benzoate (3a) [17]: white solid, 80% yield (46.1 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.15 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.0 Hz, 1H), 7.43–7.46 (m, 6H), 7.36 (t, J = 7.4 Hz, 4H), 7.30 (d, J = 7.2 Hz, 2H), 7.12 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.6, 140.4, 133.1, 130.1, 129.8, 128.6, 128.5, 128.0, 127.2, 77.5. MS (EI) m/z (%) 288, 183, 166 (100), 152, 105, 77.
Benzhydryl 4-methylbenzoate (3b) [20]: white solid, 80% yield (48.3 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.03 (d, J = 8.0 Hz, 2H), 7.27–7.44 (m, 12H), 7.10 (s, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.7, 143.9, 140.5, 129.9, 129.2, 128.6, 128.0, 127.6, 127.2, 77.3, 21.7. MS (EI) m/z (%) 302, 166 (100), 152, 119, 91.
Benzhydryl 3-methylbenzoate (3c): White solid, 84% yield (50.7 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.94 (m, 2H), 7.30–7.45 (m, 12H), 7.12 (s, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.8, 140.4, 138.3, 134.0, 132.5, 130.3, 128.6, 128.4, 128.0, 127.2, 127.0, 77.4, 21.4; MS (EI) m/z (%) 302, 166 (100), 152, 119, 91; HRMS calcd. for: C21H18NaO2 [M + Na]+: 325.1201, found m/z 325.1205.
Benzhydryl 2-methylbenzoate (3d) [21]: colorless liquid, 82% yield (49.5 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.08 (d, J = 7.6 Hz, 1H), 7.31–7.46 (m, 13H), 7.01 (s, 1H), 2.61 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.4, 140.7, 140.5, 132.2, 131.9, 130.8, 129.5, 128.6, 128.0, 127.2, 125.9, 77.4, 22.0; MS (EI) m/z (%) 302, 166 (100), 152, 119, 91.
Benzhydryl 4-fluorobenzoate (3e) [22]: colorless liquid, 70% yield (42.9 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.10 (t, J = 6.8 Hz, 2H), 7.20–7.37 (m, 10H), 7.04–7.09 (m, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.9 (d, J = 259.2 Hz), 164.7, 140.2, 132.4 (d, J = 9.3 Hz), 130.0, 128.6, 128.0, 127.2, 115.6 (d, J = 21.9 Hz), 77.7; MS (EI) m/z (%) 306, 183, 166 (100), 152, 123, 95.
Benzhydryl 2-fluorobenzoate (3f) [23]: colorless liquid, 82% yield (50.2 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.91 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.2 Hz, 4H), 7.32–7.40 (m, 8H), 7.14 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 163.5, 162.2 (d, J = 258.9 Hz), 140.2, 134.7 (d, J = 9.0 Hz), 132.4, 128.6, 128.0, 127.2, 124.1 (d, J = 4.0 Hz), 118.8, 117.1 (d, J = 22.4 Hz), 78.0; MS (EI) m/z (%) 306, 183, 166 (100), 152, 123, 95.
Benzhydryl 2-chlorobenzoate (3g) [23]: colorless liquid, 81% yield (52.3 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.93 (d, J = 7.6 Hz, 1H), 7.30–7.46 (m, 13H), 7.13 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 164.6, 140.0, 134.1, 132.7, 131.7, 131.2, 130.1, 128.6, 128.0, 127.3, 126.6, 78.4; MS (EI) m/z (%) 322, 183, 166 (100), 152, 139, 77.
Benzhydryl 2-bromobenzoate (3h) [24]: white solid, 83% yield (61.0 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.96 (t, J = 7.2 Hz, 1H), 7.10–7.48 (m, 13H), 7.07 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.1, 139.9, 134.6, 132.8, 132.0, 131.6, 128.6, 128.1, 127.3, 127.2, 122.0, 78.5. MS (EI) m/z (%) 366, 183, 167 (100), 152, 77.
Benzhydryl 2-methoxybenzoate (3i) [24]: colorless liquid, 70% yield (44.6 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.91 (d, J = 7.6 Hz, 1H), 7.28–7.50 (m, 11H), 7.10 (s, 1H), 6.97–7.00 (m, 2H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.1, 159.6, 140.6, 133.8, 132.0, 128.5, 127.8, 127.3, 126.6, 120.2, 112.2, 77.3, 56.0. MS (EI) m/z (%) 318, 183, 167 (100), 152, 135, 77.
Benzhydryl 2,4,6-trimethylbenzoate (3j): colorless liquid, 85% yield (56.2 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.30–7.43 (m, 10H), 7.17 (s, 1H), 6.84 (s, 2H), 2.29 (s, 3H), 2.17 (s, 6H); 13C NMR (100 MHz, CDCl3, ppm) δ 169.3, 140.1, 139.4, 135.2, 130.9, 128.5, 128.4, 128.0, 127.4, 77.5, 21.2, 19.7. MS (EI) m/z (%) 330, 167 (100), 155, 147, 77; HRMS calcd. for: C23H22NaO2 [M + Na]+: 353.1514, found m/z 353.1509.
Benzhydryl 3-methylthiophene-2-carboxylate (3k): colorless liquid, 88% yield (54.3 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.30–7.46 (m, 11H), 7.07 (s, 1H), 6.94 (d, J = 4.8 Hz, 1H), 2.59 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 161.7, 146.7, 140.4, 131.8, 130.3, 128.6, 127.9, 127.1, 126.7, 77.2, 16.0; MS (EI) m/z (%) 308, 167 (100), 152, 125, 77; HRMS calcd. for: C19H16NaO2S [M + Na]+: 331.0765, found m/z 331.0768.
Benzhydryl cinnamate (3l) [25]: white solid, 82% yield (51.6 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.76 (d, J = 16.0 Hz, 1H), 7.54 (m, 2H), 7.30–7.39 (m, 13H), 7.02 (s, 1H), 6.57 (d, J = 16.4 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.0, 145.4, 140.3, 134.4, 130.4, 128.9, 128.6, 128.2, 127.9, 127.2, 118.1, 77.1; MS (EI) m/z (%) 314, 268, 236, 167 (100), 131, 77.
Benzhydryl formate (3m) [26]: colorless liquid, 80% yield (34.0 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.24 (s, 1H), 7.26–7.36 (m, 10H), 7.01 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 159.9, 139.6, 128.6, 128.1, 127.2, 76.6. MS (EI) m/z (%) 212, 184, 166 (100), 152, 77.
Benzhydryl acetate (3n) [17]: colorless liquid, 93% yield (42.1 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.28–7.35 (m, 10H), 6.89 (s, 1H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 170.0, 140.3, 128.5, 127.9, 127.2, 76.9, 21.3. MS (EI) m/z (%) 226, 184, 165 (100), 152, 105, 77.
Benzhydryl pivalate (3o) [22]: white solid, 83% yield (44.5 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.30–7.36 (m, 10H), 6.84 (s, 1H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ 177.3, 140.7, 128.9, 127.8, 126.9, 76.6, 39.0, 27.2. MS (EI) m/z (%) 268, 211, 183, 167 (100), 152, 57.
Benzhydryl hexanoate (3p) [27]: colorless liquid, 82% yield (46.3 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.30–7.36 (m, 10H), 6.90 (s, 1H), 2.43 (t, J = 7.4 Hz, 2H), 1.66–1.72 (m, 2H), 1.27–1.31 (m, 4H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 172.8, 140.5, 128.5, 127.9, 127.1, 76.7, 34.6, 31.3, 24.7, 22.3, 13.9. MS (EI) m/z (%) 282, 184, 166 (100), 152, 77.
Phenyl(p-tolyl)methyl benzoate (3q) [17]: white solid, 82% yield (49.6 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.16 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.31–7.50 (m, 9H), 7.18 (d, J = 7.6 Hz, 2H), 7.11 (s, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.6, 140.5, 137.7, 137.5, 133.1, 130.5, 129.8, 129.3, 128.5, 128.4, 127.9, 127.2, 127.1, 77.4, 21.1. MS (EI) m/z (%) 302, 197, 180 (100), 165 (100), 105, 77.
Phenyl(m-tolyl)methyl benzoate (3r): colorless liquid, 80% yield (48.4 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.17 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.27–7.50 (m, 10H), 7.11–7.13 (m, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.6, 140.5, 140.3, 138.2, 133.1, 130.5, 129.8, 128.8, 128.5, 128.5, 128.4, 127.9, 127.2, 124.2, 77.6, 21.5. MS (EI) m/z (%) 302, 197, 180, 165 (100), 105, 77. HRMS calcd. for: C21H18NaO2 [M]+: m/z 325.11990, found m/z 325.12047.
Phenyl(o-tolyl)methyl benzoate (3s): colorless liquid, 88% yield (53.2 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.15 (d, J = 7.6 Hz, 2H), 7.22–7.61 (m, 13H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.6, 139.6, 138.2, 136.0, 133.1, 130.7, 130.1, 129.8, 128.5, 128.4, 128.0, 127.9, 127.5, 127.2, 126.2, 75.0, 19.5; MS (EI) m/z (%) 302, 179 (100), 165, 105, 77; HRMS calcd. for: C21H18NaO2 [M + Na]+: 325.1199, found 325.1202.
(4-Fluorophenyl)(phenyl)methyl benzoate (3t): colorless liquid, 80% yield (49.0 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.15 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 7.0 Hz, 1H), 7.33–7.51 (m, 9H), 7.13 (s, 1H), 7.06 (t, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.5, 162.5 (d, J = 245.4 Hz), 140.1, 136.2, 133.2, 132.7 (d, J = 9.0 Hz), 129.8, 129.1 (d, J = 8.0 Hz), 128.6, 128.5, 128.1, 127.0, 111.5 (d, J = 21.5 Hz), 76.8. MS (EI) m/z (%) 306, 201, 184 (100), 165, 105, 77. HRMS calcd. for: C20H15FNaO2 [M]+: m/z 329.09483, found m/z 329.09537.
(2-Fluorophenyl)(phenyl)methyl benzoate (3u): colorless liquid, 84% yield (51.5 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.15 (d, J = 7.5 Hz, 2H), 7.47–7.60 (m, 6H), 7.28–7.37 (m, 5H), 7.15 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.3, 160.1 (d, J = 246.8 Hz), 139.4, 133.2, 130.2, 129.8, 129.7 (d, J = 8.2 Hz), 128.6, 128.5, 128.1, 128.1, 127.9 (d, J = 13.2 Hz), 126.9, 124.3 (d, J = 3.6 Hz), 115.8 (d, J = 21.3 Hz), 71.8 (d, J = 2.9 Hz). MS (EI) m/z (%) 306, 184 (100), 165, 105, 77. HRMS calcd. for: C20H15FNaO2 [M]+: m/z 329.09483, found m/z 329.09526.
(4-Chlorophenyl)(phenyl)methyl benzoate (3v): colorless liquid, 78% yield (50.4 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.13 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.31–7.49 (m, 11H), 7.08 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.5, 139.9, 138.9, 133.9, 133.3, 131.5, 129.8, 128.8, 128.7, 128.6, 128.5, 128.2, 127.1, 76.8. MS (EI) m/z (%) 322, 200, 165 (100), 105, 77.
(4-Tert-butylphenyl)(phenyl)methyl benzoate (3w): colorless liquid, 76% yield (52.4 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.15 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.1 Hz, 1H), 7.44–7.47 (m, 4H), 7.29–7.37 (m, 7H), 7.11 (s, 1H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.6, 150.9, 140.5, 137.3, 133.0, 130.5, 129.8, 128.5, 128.4, 127.8, 127.1, 127.0, 125.5, 77.4, 34.6, 31.3; MS (EI) m/z (%) 344, 239, 222 (100), 207, 105, 77; HRMS calcd. for: C24H24NaO2 [M + Na]+: 367.1669, found 367.1669.
(4-Chlorophenyl)(p-tolyl)methyl benzoate (3x): colorless liquid, 72% yield (48.5 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.12 (d, J = 7.5 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.31–7.37 (m, 6H), 7.17 (d, J = 7.7 Hz, 2H), 7.05 (s, 1H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 165.5, 139.1, 138.0, 136.9, 133.8, 133.2, 130.2, 129.8, 129.4, 128.7, 128.5, 128.5, 127.1, 76.7, 21.1. MS (EI) m/z (%) 336, 214 (100), 179 (100), 165, 105, 77. HRMS calcd. for: C21H17ClNaO2 [M]+: m/z 359.08093, found m/z 359.08145.
(4-Nitrophenyl)(phenyl)methyl benzoate (3y): colorless liquid, 40% yield (26.7 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 8.22 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 8.4 Hz, 3H), 7.49 (t, J = 7.6 Hz, 2H), 7.34–7.44 (m, 5H), 7.16 (s, 1H).13C NMR (100 MHz, CDCl3, ppm) δ 165.3, 147.4, 138.9, 133.5, 130.7, 130.1, 129.8, 128.9, 128. 7, 128.6, 127.8, 127.3, 123.9, 76.5. MS (EI) m/z (%) 333, 211, 165, 105 (100), 77.
N-Benzhydrylbenzamide (4a) [28]: white solid, 62% yield (35.6 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.85 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.32–7.40 (m, 10H), 6.68 (d, J = 6.8 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.6, 141.5, 134.3, 131.7, 131.0, 128.8, 128.7, 127.6, 127.1, 57.5. MS (EI) m/z (%) 287, 182, 165, 105 (100), 77.
N-Benzhydrylbenzenesulfonamide (4b) [29]: white solid, 76% yield (49.2 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.70 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.11–7.23 (m, 10H), 5.63 (d, J = 7.2 Hz, 1H), 5.11 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 140.4, 132.4, 131.0, 128.8, 128.6, 127.7, 127.4, 127.2, 61.4. MS (EI) m/z (%) 322, 246, 182 (100), 167, 104, 77.
N-Benzhydryl-4-methylbenzenesulfonamide (4c) [29]: white solid, 70% yield (47.2 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.50 (d, J = 8.0 Hz, 2H), 7.04–7.20 (m, 12H), 5.51 (d, J = 6.8 Hz, 1H), 4.94 (d, J = 6.4 Hz, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 143.1, 140.7, 137.6, 129.3, 128.5, 127.5, 127.4, 127.2, 61.4, 21.4. MS (EI) m/z (%) 336, 182 (100), 167, 91, 77.
N-Benzhydrylmethanesulfonamide (4d) [30]: white solid, 67% yield (35.0 mg), 1H NMR (400 MHz, CDCl3, ppm) δ 7.36–7.41 (m, 10H), 5.79 (d, J = 6.8 Hz, 1H), 4.99 (d, J = 6.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 140.7, 128.9, 128.0, 127.5, 61.3, 41.9. MS (EI) m/z (%) 259, 180 (100), 165, 104, 77.

4. Conclusions

In summary, we have developed a DDQ-promoted esterification and amination of benzylic C–H bonds under metal- and iodide-free conditions. A close to equal amount of coupling reagents is enough to afford the product in good to high yields. Functional groups, such as methyl, methoxy, fluoro, chloro, and bromo, were all well tolerated under the optimized reaction conditions. This method affords an efficient alternative route for the synthesis of esters and amides. The scope, mechanism, and synthetic applications of this reaction are under investigation.

Supplementary Materials

The supplementary materials are available online.

Author Contributions

Conceptualization, S.L. and J.Z.; methodology, R.C.; writing—original draft preparation, S.L. and G.H.; writing—review and editing, S.L.

Funding

We gratefully thank the Normal Project Foundation of Hunan Provincial Education Department (18C0845), the Key Project Foundation of Hunan Provincial Education Department (18A396, 19A085), and the Natural Science Foundation of Hunan Province (2017JJ2018).

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.
Molecules 25 01527 sch001 550
Scheme 1. Radical trapping experiment.
Scheme 1. Radical trapping experiment.
Molecules 25 01527 sch001
Molecules 25 01527 sch002 550
Scheme 2. Proposed mechanism for the esterification of diarylmethanes.
Scheme 2. Proposed mechanism for the esterification of diarylmethanes.
Molecules 25 01527 sch002
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 25 01527 i001
EntryOxidant (equiv.)SolventYield b (%)
1DDQ (1.2)DCE95
2BQ (1.2)DCE0
3TBHP (1.2)DCE0
4tBuOOtBu (1.2)DCE0
5H2O2 (1.2)DCE0
6dicumyl peroxide (1.2)DCE0
7DDQ (1.2)CHCl394
8DDQ (1.2)CH2Cl293
9DDQ (1.2)Cl2CHCHCl280
10DDQ (1.2)EtOAc10
11DDQ (1.2)CH3CN12
12DDQ (1.2)H2O0
13DDQ (1.2)pyridine0
14cDDQ (1.2)DCE72
15dDDQ (0.5)DCE51
16eDDQ (1.2)DCE70
17fDDQ (1.2)DCE84
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), solvent (0.6 mL), 100 °C, 8 h, under argon. b GC yield based on 1a. c At 80 °C. d Under O2, 45% benzophenone was detected. e Under air, 28% benzophenone was detected. f 0.2 mmol of 2a was used.
Table
Table 2. Reaction of 1a with various carboxylic acids and amines a.
Table 2. Reaction of 1a with various carboxylic acids and amines a.
Molecules 25 01527 i002
Molecules 25 01527 i003 Molecules 25 01527 i004 Molecules 25 01527 i005 Molecules 25 01527 i006
Molecules 25 01527 i007 Molecules 25 01527 i008 Molecules 25 01527 i009 Molecules 25 01527 i010
Molecules 25 01527 i011 Molecules 25 01527 i012 Molecules 25 01527 i013 Molecules 25 01527 i014
Molecules 25 01527 i015 Molecules 25 01527 i016 Molecules 25 01527 i017 Molecules 25 01527 i018
Molecules 25 01527 i019 Molecules 25 01527 i020 Molecules 25 01527 i021 Molecules 25 01527 i022
a Reaction conditions: 1a (0.2 mmol), carboxylic acids and amines (0.3 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.24 mmol), 1,2-dichloroethane (DCE) 0.6 mL, 100 °C, 8 h, under argon, isolated yield.
Table
Table 3. Esterification of various diarylmethanes a.
Table 3. Esterification of various diarylmethanes a.
Molecules 25 01527 i023
Molecules 25 01527 i024 Molecules 25 01527 i025 Molecules 25 01527 i026
Molecules 25 01527 i027 Molecules 25 01527 i028 Molecules 25 01527 i029
Molecules 25 01527 i030 Molecules 25 01527 i031 Molecules 25 01527 i032
a Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), DDQ (0.24 mmol), DCE 0.6 mL, 100 °C, 8 h, under argon, isolated yield.

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Liu, S.; Chen, R.; He, G.; Zhang, J. An Efficient Metal-Free Oxidative Esterification and Amination of Benzyl C–H Bond. Molecules 2020, 25, 1527. https://doi.org/10.3390/molecules25071527

AMA Style

Liu S, Chen R, He G, Zhang J. An Efficient Metal-Free Oxidative Esterification and Amination of Benzyl C–H Bond. Molecules. 2020; 25(7):1527. https://doi.org/10.3390/molecules25071527

Chicago/Turabian Style

Liu, Saiwen, Ru Chen, Guowen He, and Jin Zhang. 2020. "An Efficient Metal-Free Oxidative Esterification and Amination of Benzyl C–H Bond" Molecules 25, no. 7: 1527. https://doi.org/10.3390/molecules25071527

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