Decarboxylative acylation of arenes with mandelic acid derivatives via palladium-catalyzed oxidative sp² C–H activation

Abstract

An efficient palladium catalyzed decarboxylative acylation of arenes with mandelic acid derivatives via oxidative sp² C–H activation in the presence of tert-butyl hydroperoxide has been developed. The acylation reaction is assisted by a pyridine directing group. The starting materials are inexpensive and readily available. This method provides an economical and convenient way to synthesize aryl ketones.

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Introduction

Aryl ketones are important intermediates in the synthesis of drugs, dyes, pesticides and other fine chemicals.¹ The Friedel–Crafts acylation of aromatic compounds is the classical route to synthesize aryl ketones.² This method usually requires harsh reaction conditions, and the reaction produces hazardous reagents. In addition, the reaction typically requires electron-rich aromatic substrates since electron-deficient aromatic substrates do not easily react. Thus much research has been devoted to developing efficient alternative routes to synthesize aryl ketones.

In recent years, transition-metal-catalyzed C–H bond activation with subsequent functionalization has been widely used in organic chemistry and this has produced many appealing results.³ The activation of C–H bonds has obvious advantages, but it also produces challenges. For example, organic molecules usually contain multiple bonds with dissociation energies that are similar to the C–H bonds. So selectively activating a specific C–H bond is a major problem.

Some substrates like indole have specific electronic effects whereby they can selectively activate a C–H bond. However, for most substrates, a directing group needs to be introduced. The directing group forms coordination compounds with transition-metal catalysts to control the selective functionalization of the molecule. Recently, the direct selective functionalization of arenes by C–H bond activation has attracted considerable attention since this is an environmentally friendly alternative for aryl ketone synthesis.⁴ A representative example is transition-metal-catalyzed oxidative sp² C–H bond acylations with aldehydes.^5,6

Transition-metal-catalyzed decarboxylative coupling reactions are very attractive since these reactions do not require the use of stoichiometric organometallic reagents and they do not generate toxic metal salt wastes.^7,8 In addition, the raw materials are inexpensive and readily available. In 2010, Ge et al.⁹ reported the palladium-catalyzed ortho-decarboxylative acylation of 2-arylpyridines and acetanilides with α-oxocarboxylic acids. Two years later, Wang demonstrated the decarboxylative acylation cyclic of enamides with α-oxocarboxylic acids in the presence of palladium catalysis.¹⁰ The palladium-catalyzed decarboxylative acylation of azobenzenes with α-oxocarboxylic acids was developed by Wang in 2013.¹¹ In the same year, Tan,¹² Kim,¹³ Wang¹⁴ and Zhang¹⁵ reported respectively the palladium-catalyzed decarboxylative acylation of oximes, phenylacetamides, azoxybenzenes, and 2-aryloxypyridines with α-oxocarboxylic acids. All these methods provided a novel way to synthesize aryl ketones.

Mandelic acid and its derivatives are important building blocks in bioactive compounds.¹⁶ They have been widely used as starting material and reagents for synthetic purposes.¹⁷ Many derivatives are commercially available. Herein, a palladium-catalyzed decarboxylative acylation of arenes with mandelic acid derivatives via C–H activation in the presence of tert-butyl hydroperoxide (TBHP) as an oxidant is described. This method has fewer reaction steps than previously reported methods.

Experimental

General information

¹H NMR spectra were obtained on a 400 or 600 MHz spectrometer and ¹³C NMR spectra were obtained on a 600 MHz spectrometer with CDCl₃ as the solvent. All ¹H NMR and ¹³C NMR chemical shifts are referenced to the residual ¹H and ¹³C solvent (relative to TMS) and are reported in units of ppm. GC-Mass spectra were recorded on a Luniere Tech. Ltd TRACEDSQ instrument. Unless otherwise noted, all reactions were performed in air. Reactions were monitored by analytical thin layer chromatography on 0.20 mm Anhui Liangchen silica gel plates. Silica gel (200–300 mesh) (from Anhui Liangchen Chem. Company, Ltd.) was used for flash chromatography. Arylpyridines¹⁸ and the mandelic acids derivatives¹⁹ were prepared according to the relevant literature procedures. The other chemicals or reagents were obtained from commercial sources and used directly.

General procedure for the preparation of 3 and 4

Pd(OAc)₂ (2.2 mg, 0.01 mmol), 1a–o (or 1a) (0.2 mmol), 2a (or 2b–k) (0.4 mmol) and TBHP (70% aqueous solution, 1.0 mmol) were placed in a 10 mL glass vial. The vial was immersed in an oil bath at 120 °C and the reaction mixture was stirred for 20 h. The reaction temperature was then lowered to room temperature and the mixture was extracted with methylene chloride (3 × 5 mL). The combined organic layers were dried over magnesium sulfate and the solvent was then evaporated and the residue was purified by column chromatography on silica gel.

Phenyl(2-(pyridin-2-yl)phenyl)methanone (3a)^5b. A light yellow solid. Yield: 82%. ¹H NMR (600 MHz, CDCl₃) δ (ppm): 6.99 (t, 1H), 7.25 (t, 2H), 7.36–7.39 (t, 1H), 7.48 (m, 5H), 7.68 (d, 2H), 7.76 (d, J = 7.8 Hz, 1H), 8.35 (d, 1H). ¹³C NMR (150 MHz, CDCl₃) δ (ppm): 198.2, 156.8, 149.1, 139.7, 139.5, 137.9, 136.3, 132.3, 130.2, 129.5, 129.1, 128.8, 128.5, 128.0, 122.6, 121.9. Analytical data calcd (found) for C₁₈H₁₃NO: C, 83.37 (83.86); H, 5.05 (4.97).

(5-Methyl-2-(pyridin-2-yl)phenyl)(phenyl)methanone (3b)²⁰. A pale yellow solid. Yield: 90%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 2.45 (s, 3H), 6.96 (t, J = 8.0 Hz, 1H), 7.24 (t, J = 8.4 Hz, 2H), 7.34 (m, 5H), 7.66 (t, J = 8.0 Hz, 3H), 8.33 (d, J = 4.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 198.5, 156.7, 148.9, 139.4, 138.7, 138.0, 136.8, 136.2, 132.2, 130.9, 129.6, 129.4, 128.6, 128.0, 122.5, 121.7, 21.2. Analytical data calcd (found) for C₁₉H₁₅NO: C, 83.49 (83.26); H, 5.53 (5.32).

(3-Methyl-2-(pyridin-2-yl)phenyl)(phenyl)methanone (3c)²⁰. A light yellow solid. Yield: 85%. ¹H NMR (400 MHz, CDCl₃): δ (ppm): 2.26 (s, 3H), 7.01 (m, 1H), 7.24 (m, 3H), 7.34 (m, 4H), 7.42 (m, 1H), 7.61 (m, 2H), 8.42 (m, 1H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm): 198.5, 157.5, 149.1, 139.8, 139.3, 137.6, 136.7, 135.0, 132.5, 132.5, 129.9, 127.9, 127.7, 126.3, 125.3, 121.7, 20.1. Analytical data calcd (found) for C₁₉H₁₅NO: C, 83.49 (83.66); H, 5.53 (5.48).

(4-Methyl-2-(pyridin-2-yl)phenyl)(phenyl)methanone (3d)²⁰. A light yellow solid. Yield: 78%. ¹H NMR (600 MHz, CDCl₃) δ (ppm): 2.50 (s, 3H), 7.01 (t, 1H), 7.24 (t, 1H), 7.33 (m, 7H), 7.66 (d, J = 7.2 Hz, 2H), 8.40 (d, 1H). ¹³C NMR (150 MHz, CDCl₃) δ (ppm): 198.3, 157.2, 149.1, 140.6, 139.9, 138.0, 136.6, 136.2, 132.3, 130.1, 129.8, 129.6, 129.4, 129.1, 128.4, 128.0, 21.5. Analytical data calcd (found) for C₁₉H₁₅NO: C, 83.49 (84.26); H, 5.53 (5.25).

(5-Methoxy-2-(pyridin-2-yl)phenyl)(phenyl)methanone (3e)²⁰. A pale yellow solid. Yield: 85%. ¹H NMR (400 MHz, CDCl₃): δ (ppm): 3.85 (s, 3H), 6.91 (m, 1H), 7.05 (d, J = 2.0 Hz, 1H), 7.10 (m, 1H), 7.23 (m, 2H), 7.34 (m, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.48 (m, 1H), 7.68 (m, 3H), 8.28 (d, J = 4.4 Hz, 1H). ¹³C NMR (CDCl₃, 100 MHz): δ197.7, 159.7, 156.1, 148.7, 140.7, 137.6, 136.1, 132.2, 131.8, 129.8, 129.2, 127.9, 121.9, 121.2, 115.9, 113.9, 55.4. Analytical data calcd (found) for C₁₉H₁₅NO₂: C, 78.87 (77.96); H, 5.23 (5.28).

(3-Methoxy-2-pyridin-2-yl-phenyl)-phenyl-methanone (3f)²⁰. A light yellow solid. Yield: 92%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.83 (s, 3H), 6.93 (m, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.23 (m, 2H), 7.35 (m, 1H), 7.42 (m, 1H), 7.49 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 8.33 (d, J = 4.8 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 197.4, 156.5, 154.1, 148.6, 141.6, 137.6, 135.1, 132.1, 129.3, 129.2, 128.6, 127.7, 125.9, 121.5, 121.0, 112.8, 55.8. Analytical data calcd (found) for C₁₉H₁₅NO₂: C, 78.87 (78.41); H, 5.23 (5.67).

(4-Methoxy-2-pyridin-2-yl-phenyl)-phenyl-methanone (3g)²⁰. A light yellow solid. Yield: 95%. ¹H NMR (600 MHz, CDCl₃) δ (ppm): 3.90 (s, 3H), 6.97 (m, 2H), 7.20 (m, 3H), 7.31 (m, 2H), 7.47 (m, 2H), 7.64 (d, J = 7.6 Hz, 2H), 8.37 (d, J = 4.0 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ (ppm): 197.4, 161.0, 156.92, 149.0, 142.1, 138.2, 136.0, 131.9, 131.6, 131.3, 129.3, 127.8, 123.1, 121.9, 114.4, 113.6, 55.4. Analytical data calcd (found) for C₁₉H₁₅NO₂: C, 78.87 (78.52); H, 5.23 (5.13).

(5-Fluoro-2-pyridin-2-yl-phenyl)-phenyl-methanone (3h)²⁰. A light yellow solid. Yield: 90%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.98 (m, 1H), 7.24 (m, 4H), 7.38 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.54 (m, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.74 (m, 1H), 8.31 (d, J = 4.4 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 196.4, 162.5, 155.6, 148.9, 141.4, 137.2, 136.3, 135.6, 132.5, 130.5, 129.3, 128.1, 122.3, 121.9, 116.8, 116.5. Analytical data calcd (found) for C₁₈H₁₂FNO: C, 77.97 (77.64); H, 4.36 (4.32).

(5-Chloro-2-pyridin-2-yl-phenyl)-phenyl-methanone (3i)²⁰. A light yellow solid. Yield: 81%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.97 (m, 1H), 7.25 (m, 2H), 7.37 (m, 1H), 7.47 (m, 4H), 7.67 (m, 3H), 8.30 (d, J = 4.0 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 196.4, 155.3, 148.9, 140.8, 137.7, 137.2, 136.3, 134.6, 132.5, 130.0, 129.8, 129.2, 128.8, 128.0, 122.2, 122.1. Analytical data calcd (found) for C₁₈H₁₂ClNO: C, 73.6 (73.55); H, 4.12 (4.01).

(5-Bromo-2-pyridin-2-yl-phenyl)-phenyl-methanone (3j)^5b. A pale yellow solid. Yield: 73%. ¹H NMR (600 MHz, CDCl₃) δ (ppm): 7.03 (t, 1H), 7.27 (t, J = 7.8 Hz, 2H), 7.39 (t, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 3.8 Hz, 1H), 7.64 (m, 5H), 8.34 (d, J = 4.2 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃) δ (ppm): 196.5, 155.6, 149.1, 141.2, 138.4, 137.3, 136.5, 133.1, 132.6, 131.8, 130.2, 129.4, 128.2, 122.9, 122.4, 122.2. Analytical data calcd (found) for C₁₈H₁₂BrNO: C, 63.92 (64.01); H, 3.58 (3.48).

(4-Nitro-2-pyridin-2-yl-phenyl)-phenyl-methanone (3k). A pale pink solid. Yield: 48%. ¹H NMR (400 MHz, CDCl₃): δ (ppm): 7.13 (t, 1H), 7.32 (t, 2H), 7.38 (t, 1H), 7.61 (t, 2H), 7.85 (t, 1H), 8.18 (d, 1H), 8.30 (d, 1H), 8.38 (m, 2H), 8.69 (d, 1H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm): 197.2, 157.5, 154.2, 149.2, 145.2, 144.1, 137.0, 136.8, 133.1, 131.7, 130.2, 128.4, 124.7, 123.6, 122.5. Analytical data calcd (found) for C₁₈H₁₂N₂O₃: C, 71.05 (71.33); H, 3.97 (3.95). HRMS (ESI) m/z: 305.0926 [M + H]⁺ (calcd 305.0925).

Ethyl-3-benzoyl-4-(pyridin-2-yl)benzoate (3l)^6c. A light yellow solid. Yield: 84%. ¹H NMR (400 MHz, CDCl₃): δ (ppm): 1.40 (t, 3H), 4.40 (q, 2H), 7.10 (t, 1H), 7.28 (t, 2H), 7.41 (t, 1H), 7.55 (d, 1H), 7.62 (m, 2H), 8.11 (d, 1H), 8.23 (m, 3H), 8.44 (d, 1H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm): 200.5, 165.7, 155.6, 148.9, 143.0, 139.7, 137.4, 136.9, 132.6, 131.2, 131.1, 130.0, 128.9, 128.2, 123.1, 122.7, 61.4, 14.3. Analytical data calcd (found) for C₂₁H₁₇NO₃: C, 76.12 (76.77); H, 5.17 (4.97).

Ethyl-3-benzoyl-2-(pyridin-2-yl)benzoate (3m). A light yellow solid. Yield: 93%. ¹H NMR (400 MHz, CDCl₃): δ (ppm): 2.04 (t, 3H), 4.93 (q, 2H), 6.91 (t, 1H), 7.03 (d, 1H), 7.25 (m, 3H), 7.53 (m, 1H), 7.72 (m, 4H), 7.94 (d, 1H), 8.53 (d, 1H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm): 200.4, 167.5, 160.0, 154.7, 145.8, 137.8, 137.4, 137.2, 135.0, 134.4, 132.1, 131.5, 128.8, 128.5, 126.1, 123.0, 121.5, 65.6, 14.1. Analytical data calcd (found) for C₂₁H₁₇NO₃: C, 76.12 (75.96); H, 5.17 (5.09). HRMS (ESI) m/z: 354.1105 [M + Na]⁺ (calcd 354.1101).

1-(3-Benzoyl-4-pyridin-2-yl-phenyl)-ethanone (3n)²⁰. A light yellow solid. Yield: 81%. ¹H NMR (400 MHz, CDCl₃) δ: 2.87 (s, 3H), 7.07 (m, 1H), 7.27 (m, 2H), 7.40 (m, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.61 (m, 1H), 7.68 (m, 2H), 7.89 (d, 1H), 8.10 (d, 1H), 8.19 (dd, J = 1.8, 8.1 Hz, 1H), 8.40 (d, J = 4.6 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ: 197.8, 197.5, 156.1, 149.9, 143.6, 139.9, 137.2, 137.0, 136.6, 132.5, 130.9, 129.0, 128.8, 127.5, 127.1, 122.9, 121.1, 26.7. Analytical data calcd (found) for C₂₀H₁₅NO₂: C, 79.72 (79.52); H, 5.02 (5.18).

Benzo[h]quinolin-10-yl(phenyl)-methanone (3o)²⁰. A light yellow solid. Yield: 94%. ¹H NMR (400 MHz, CDCl₃) δ: 7.31 (m, 3H), 7.42 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.75 (m, 4H), 7.91 (d, J = 8.8 Hz, 1H), 8.06 (m, 2H), 8.52 (d, J = 4.0 Hz, 1H), 8.40 (d, 1H). ¹³C NMR (100 MHz, CDCl₃) δ: 198.7, 147.1, 144.6, 139.2, 138.9, 135.3, 133.8, 131.7, 129.0, 128.7, 128.5, 12.8.1, 127.8, 127.7, 127.0, 126.4, 126.1, 121.7. Analytical data calcd (found) for C₂₀H₁₃NO: C, 84.78 (85.45); H, 4.62 (4.51).

(2-Pyridin-2-yl-phenyl)-o-tolyl-methanone (4b)^5b. A pale yellow solid. Yield: 70%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 2.60 (s, 3H), 6.90 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 7.13 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.48 (m, 3H), 7.61 (m, 2H), 8.41 (d, J = 4.4 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 199.7, 157.3, 148.6, 140.6, 140.1, 139.0, 138.0, 136.0, 131.1, 130.8, 130.3, 130.2, 129.6, 128.9, 128.3, 124.6, 122.3, 121.6, 20.8. Analytical data calcd (found) for C₁₉H₁₅NO: C, 83.49 (83.67); H, 5.53 (5.42).

(2-Pyridin-2-yl-phenyl)-p-tolyl-methanone (4c)²⁰. A pale yellow solid. Yield: 82%. ¹H NMR (400 MHz, CDCl₃): δ (ppm): 2.33 (s, 3H), 7.28 (d, 3H), 7.48 (m, 7H), 7.78 (d, J = 7.6 Hz, 1H), 8.47 (d, 1H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm): 197.8, 156.9, 148.8, 143.2, 136.6, 135.2, 130.2, 130.1, 129.8, 129.2, 129.1, 129.0, 128.8, 128.5, 123.2, 122.1, 21.7. Analytical data calcd (found) for C₁₉H₁₅NO: C, 83.49 (84.01); H, 5.53 (5.36).

(4-Methoxyphenyl)-(2-(pyridin-2-yl)-phenyl)-methanone (4d)²⁰. A pale yellow solid. Yield: 68%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.74 (s, 3H), 6.73 (d, J = 8.4 Hz, 2H), 6.98 (m, 1H), 7.44 (m, 5H), 7.65 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 196.8, 162.8, 156.8, 148.9, 139.6, 139.3, 136.1, 131.7, 130.6, 129.8, 128.8, 128.6, 128.2, 122.7, 121.7, 113.2, 55.2. Analytical data calcd (found) for C₁₉H₁₅NO₂: C, 78.87 (78.33); H, 5.23 (5.12).

(4-Fluorophenyl)-(2-(pyridin-2-yl)-phenyl)-methanone (4e)²⁰. A pale yellow solid. Yield: 85%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.90 (m, 2H), 7.01 (m, 1H), 7.49 (m, 3H), 7.56 (m, 2H), 7.68 (m, 2H), 7.76 (d, J = 7.6 Hz, 1H), 8.34 (d, J = 4.8 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 196.6, 165.1, 156.6, 148.9, 139.4, 139.2, 136.3, 134.4, 131.8, 130.2, 128.9, 128.7, 128.5, 122.5, 122.0, 115.0. Analytical data calcd (found) for C₁₈H₁₂FNO: C, 77.97 (77.87); H, 4.36 (4.28).

(4-Chlorophenyl)-(2-(pyridin-2-yl)-phenyl)-methanone (4f)²⁰. A pale yellow solid. Yield: 82%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.06 (m, 1H), 7.23 (d, 2H), 7.51 (m, 7H), 7.77 (d, 1H), 8.38 (d, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 196.9, 156.4, 148.9, 139.3, 139.1, 138.6, 136.7, 136.3, 130.8, 130.3, 129.0, 128.8, 128.7, 128.4, 122.7, 122.2. Analytical data calcd (found) for C₁₈H₁₂ClNO: C, 73.60 (73.91); H, 4.12 (4.08).

(4-Bromophenyl)-(2-(pyridin-2-yl)-phenyl)-methanone (4g)²⁰. A pale yellow solid. Yield: 83%. ¹H NMR (400 MHz, CDCl₃): δ (ppm): 7.04 (t, 1H), 7.40 (d, 2H), 7.53 (m, 7H), 7.77 (d, J = 7.7 Hz, 1H), 8.35 (d, 1H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm): 196.5, 156.4, 148.9, 139.3, 139.1, 136.9, 136.6, 131.3, 130.8, 130.3, 129.0, 128.7, 128.6, 127.3, 122.4, 122.2. Analytical data calcd (found) for C₁₈H₁₂BrNO: C, 63.92 (63.55); H, 3.58 (3.61).

(2-Chlorophenyl)-(2-(pyridin-2-yl)-phenyl)-methanone (4h)²¹. A pale yellow solid. Yield: 73%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.05 (t, J = 6.0 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.54 (m, 7H), 7.79 (d, J = 7.7 Hz, 1H), 8.36 (d, J = 4.4 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 196.5, 155.4, 149.2, 142.8, 142.8, 140.2, 137.3, 136.5, 132.7, 129.4, 129.2, 128.2, 126.8, 126.7, 126.0, 125.9, 122.8, 122.6. Analytical data calcd (found) for C₁₈H₁₂ClNO: C, 73.60 (73.16); H, 4.12 (3.97).

(2-Brophenyl)-(2-(pyridin-2-yl)-phenyl)-methanone (4i)²⁰. A pale yellow solid. Yield: 88%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.96 (m, 3H), 7.21 (m, 1H), 7.41 (m, 7H), 8.50 (d, J = 4.1 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 196.7, 157.2, 149.1, 140.7, 139.6, 138.9, 136.3, 134.0, 131.7, 131.3, 131.1, 130.6, 129.4, 128.7, 126.5, 122.8, 121.9, 121.5. Analytical data calcd (found) for C₁₈H₁₂BrNO: C, 63.92 (64.26); H, 3.58 (3.28).

(4-Nitro-phenyl)-(2-pyridin-2-yl-phenyl)-phenyl-methanone (4j)²¹. A pale yellow solid. Yield: 48%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.01 (q, J = 4.5 Hz, 1H), 7.56 (m, 5H), 7.78 (m, 3H), 8.06 (m, 2H), 8.24 (d, J = 4.8 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 196.1, 155.7, 149.5, 148.7, 143.3, 139.2, 138.5, 136.9, 130.9, 129.7, 129.3, 129.1, 128.3, 123.3, 122.4, 122.0. Analytical data calcd (found) for C₁₈H₁₂N₂O₃: C, 71.05 (71.42); H, 3.97 (4.08).

(3-Nitro-phenyl)-(2-pyridin-2-yl-phenyl)-phenyl-methanone (4k)²¹. A light yellow solid. Yield: 42%. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.99 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.56 (m, 5H), 7.81 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 8.18 (m, 2H), 8.43 (s, 1H). ¹³C NMR (100 MHz, CDCl₃) δ (ppm): 195.6, 155.9, 148.7, 148.0, 139.9, 139.4, 138.3, 136.8, 134.5, 130.9, 129.3, 129.2, 129.1, 128.5, 126.3, 123.7, 122.3, 122.1. Analytical data calcd (found) for C₁₈H₁₂N₂O₃: C, 71.05 (71.26); H, 3.97 (3.28).

Results and discussion

First 2-phenylpyridine (1a) was coupled with mandelic acid (2a) in the presence of 5 mol% of catalyst in a mixed solvent of 1,4-dioxane/AcOH/DMSO (7.5/1.5/1, v/v/v) (Table 1). Pd(II) complexes are effective catalysts for the carbo-functionalization of aryl C–H bonds. Therefore, Pd(OAc)₂ was our initial choice for the catalyst and Ag₂CO₃ (3 eq.) was used as the oxidant. The reaction was conducted for 20 h at 120 °C with stirring and the desired product 3a was isolated in a low yield of only 36% (entry 1).

Table 1 Optimization of the catalyst, the oxidant and the solvent^a

Entry	Catalyst	Oxidant	Co-oxidant	Solvent	Yield^c (%)
a Reaction conditions: 2-phenylpyridine 1a (0.2 mmol), mandelic acid 2a (0.4 mmol), catalyst (5 mol%), 120 °C, 20 h in air (entries 8 and 9 in oxygen).b 1,4-Dioxane/AcOH/DMSO (7.5/1.5/1, v/v/v, c = 0.1 M).c Isolated yield.d Yield determined by GC-MS.
1	Pd(OAc)2	Ag2CO3 (3 eq.)		1,4-Dioxane/AcOH/DMSO^b	36
2	Pd(OAc)2	Ag2O (3 eq.)		1,4-Dioxane/AcOH/DMSO^b	42
3	Pd(OAc)2	Ag2O (2 eq.)	K2S2O8 (2 eq.)	1,4-Dioxane/AcOH/DMSO^b	52
4	Pd(OAc)2	Ag2O (1 eq.)	K2S2O8 (2 eq.)	1,4-Dioxane/AcOH/DMSO^b	Trace^d
5	Pd(OAc)2	Ag2O (2 eq.)	K2S2O8 (1 eq.)	1,4-Dioxane/AcOH/DMSO^b	76
6	PdCl2	Ag2O (2 eq.)	K2S2O8 (1 eq.)	1,4-Dioxane/AcOH/DMSO^b	61
7	None	Ag2O (2 eq.)	K2S2O8 (1 eq.)	1,4-Dioxane/AcOH/DMSO^b	0
8	Pd(OAc)2	O2 (1 atm)		1,4-Dioxane/AcOH/DMSO^b	Trace^d
9	PdCl2	O2 (1 atm)		PhCl	Trace^d
10	Pd(OAc)2	TBHP (3 eq.)		PhCl	67
11	PdCl2	TBHP (3 eq.)		PhCl	53
12	Pd(OAc)2	TBHP (3 eq.)		Xylene	58
13	Pd(OAc)2	TBHP (3 eq.)		Diglyme	61
14	Pd(OAc)2	TBHP (3 eq.)		DMSO	56
15	None	TBHP (3 eq.)		PhCl	0
16	Pd(OAc)2	TBHP (3 eq.)		Neat	74
17	Pd(OAc)2	TBHP (5 eq.)		Neat	82

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Next the Ag₂CO₃ was replaced with Ag₂O as the oxidant and the yield only increased to 42% (entry 2). Different ratios of oxidant to co-oxidant were tested (entries 3–5) and the best results (76% yield) were obtained for 1 eq. of K₂S₂O₈ as co-oxidant with 2 eq. of Ag₂O (entry 5). When the catalyst was changed to PdCl₂ and the other conditions remain unchanged, the yield did not improve (entry 6). When O₂ was used as the oxidant, only trace yields were obtained no matter which catalyst or solvent was used (entries 8 and 9). When no catalyst was used, the reaction did not proceed (entries 7 and 15). Next 3 eq. of TBHP was used as the oxidant with no solvent and with Pd(OAc)₂ as the catalyst. This produced a coupling yield of 74%, (entry 16). Using TBHP with a solvent like PhCl, xylene, diglyme, or DMSO, did not further improve the yield (entries 10–14). When the loading of TBHP was increased to 5 eq., a high yield (82%) was obtained (entry 17). Based on these results, 5.0 eq. TBHP and 5.0% (mol) Pd(OAc)₂ were chosen as the optimal conditions.

A variety of substituted 2-phenylpyridines (1a–o) were tested in the coupling reaction and the results are shown in Table 2. A number of functional groups on the phenyl rings including methyl, methoxyl, fluoro, chloro, bromo, nitro, ethoxycarbonyl and acetyl groups gave good to high yields of the corresponding carboacylation products under the optimal reaction conditions (73–95%, 3a–3j, 81–93%, 3l–3n). These results show that the reaction is not sensitive to the electronic properties of the phenylpyridines substituents since both electron-donating and electron-withdrawing groups reacted. It is notable that 1k which contains m-NO₂ reacted to give a moderate yield (48% of 3k) and benzo[h]quinoline (1o) produced a yield of 94% of 3o.

Table 2 Scope of 2-phenylpyridines^a,b

a Conditions: 1a–o (0.2 mmol), mandelic acid 2a (0.4 mmol), Pd(OAc)₂ (5 mol%), TBHP (1.0 mmol), 120 °C, 20 h in air.b Isolated yields.c 1o is benzo[h]quinoline.

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The effects of substituents on the mandelic acid were then studied (Table 3). The reaction proceeded smoothly for 2-phenylpyridine (1a) and mandelic acids (2b–2i) bearing different substituted groups on the benzene rings including methyl, methoxyl, fluoro, chloro, and bromo groups. The products (4b–4i) were obtained in good yields (68–88%). The position of the substituent on the mandelic acid phenyl ring only had a slight effect on the reaction yield. It is important to note that moderate yields (4j, 48% and 4k, 42%) were still obtained when the strong electron-withdrawing group, NO₂, was on the mandelic acid phenyl ring.

Table 3 Scope of mandelic acids^a,b

a Conditions: 1a (0.2 mmol), 2b–k (0.4 mmol), Pd(OAc)₂ (5 mol%), TBHP (1.0 mmol), 120 °C, 20 h in air.b Isolated yields.

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On the basis of the experimental results and previous literature, a plausible mechanism is illustrated in Scheme 1. First the palladium catalyst reacts with 2-phenylpyridine by a chelation-directed C–H activation to form intermediate (A) (step (i)). The reaction of 2 with TBHP generates intermediate B, along with the release of CO₂. With the aid of TBHP, the benzaldehyde forms acyl radical (C). This process is radical-mediated decarboxylation followed by oxidation. A similar reaction mechanism has been reported by Li and Sun.^5,6c In step (ii), intermediate (A) reacts with acyl radical (C) to form either the reactive Pd(IV) or the dimeric Pd(III).^22,6c The final step (iii) consists of the reductive elimination of intermediate D to release the product 4 and to regenerate Pd(II) for subsequent catalytic cycles.

Scheme 1 Plausible reaction mechanism.

Conclusions

An efficient approach for the palladium catalyzed decarboxylative cross-coupling of electron-deficient arenes with mandelic acid in the presence of TBHP as an oxidant has been developed. This method is capable of the direct acylation of sp² C–H bonds.

Acknowledgements

Financial support from National Nature Science Foundation of China (NSFC 21102102, 21072149, and 20872108) is gratefully acknowledged.

Notes and references

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