The Preparation of 2-(2-Oxo-2-Phenylethyl) Benzoic Acids from Dilithiated Ortho-Toluic Acid.

Abstract

ortho-Toluic acid was dimetalated with excess lithium diisopropylamide, and the resulting intermediate was condensed with a variety of aromatic esters to afford new substituted 2-(2-oxo-2-phenylethyl)benzoic acids (ortho-phenacylbenzoic acids).

Notes

Chemical Abstracts currently names these materials as 2-(2-oxo-2-phenylethyl)benzoic acids. Their former reference was α-benzoyl-o-toluic acids. Other names used for these compounds have included o-phenacylbenzoic acids. We are using the latter designation. In addition, 1H-2-benzopyranon-1-ones are referred to as isocoumarins, and 1-oxo-2,5-dihydro 1H-2,3-benzodiazepines are referred to as 2,3-benzodiazepin-1-ones in this paper.

o-Toluic acid and esters were obtained from Aldrich Chemical Co.

o-Phenacylbenzoic acid (1.00 gram) was dissolved in hot glacial acetic acid (10–15 mL), and then treated with 5–10 drops of concentrated sulfuric acid. The color of the solution darkened immediately and after 2 minutes of heating and stirring, the solution was poured into a beaker containing approximately 100 g. of ice. After the ice melted, the mixture containing solid material was filtered, and the resulting solid isocoumarin was recrystallized from alcohol or alcohol and water. See also:

o-Phenacylbenzoic acid (1.00 g.) was mixed with 1.00 g. of methylhydrazine, [5 drops of water] 10–15 mL of 2-ethoxyethanol, and heated under reflux overnight (12 hr. minimum, solution occurred). After evaporation of the 2-ethoxyethanol solvent, the resulting solid was recrystallized from ethanol. See also:

The principal electrophilic reagent used in the condensation is monolithiated 2- or 4-hydroxybenzoate.

Microanalysis for C, H, and N, when applicable were obtained from Quantitative Technologies, Inc., Box 470, Salem Industrial Park, Whitehouse, NJ 08888 [Compd. No. from Table]. Calcd. for 2, C₁₇H₁₆O₅.H₂O (C₁₇H₁₈O₆): C, 64.14; H, 5.70. Found: C, 64.13; H, 5.65. Calcd. for 3: C, 70.31; H, 4.72. Found: C, 70.22; H, 4.72. Calcd. for 4: C, 70.31; H, 4.72. Found: C, 70.18; H, 4.90. Calcd. for 5: C, 65.58; H, 4.04. Found: C, 65.82; H, 4.27. Calcd for 6: C, 77.00; H, 6.80. Found: C, 76.84; H, 6.69. Calcd. for 7: C, 67.99; H, 5.37. Found: C, 67.74; H, 5.35. Calcd. for 8: C, 61.98; H, 3.81. Found: C, 62.12; H, 3.75. Calcd. for 9: C, 65.45; H, 5.49. Found: C, 65.59; H, 5.65. Calcd. for 10, C₁₆H₁₃CIO₄.H₂O (C₁₆H₁₅ClO₅): C, 59.54; H, 4.68. Found: C, 59.51; H, 4.80. Calcd. for 11: C, 69.22; H, 5.16. Found: C, 68.98; H, 5.17. Calcd. for 12: C, 67.03; H, 3.87. Found: C, 66.95; H, 3.73. Calcd. for 13: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.42; H, 5.87; N, 8.96. Calcd. for 14: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.03; H, 5.19; N, 10.29.

Infrared spectra were obtained from a Mattson Polaris FT-Infrared Spectrometer. Each compound 1–10 displayed less defined but somewhat characteristic OH absorptions observed for carboxylic acids between 3400–3200 and 2700 -2500 cm⁻¹. ¹H nmr for 1 and 4 – 14 were obtained from a Varian Associates, EM-360L and 1 and 3 from a EM-360A Nuclear Magnetic Resonance Spectrometers, and chemical shifts are reported in δ ppm downfield from an internal tetramethylsilane (TMS) standard. [Compd. No.: ir (paraffin oil), cm⁻¹; ¹H nmr (solvent), δ ppm] Compd. 1: ir, 3150 (broad, OH), 1687 (C=O-O), and 1672 (C=O-CH₂); nmr (CDCl₃/DMSO-d₆), 4.86 (s, CH₂-C=O) and 7.20–8.37 (m, AH). Compd. 2: ir, 3509 and 3430 (OH), 1711 (C=O-O), and 1672 (C=O-CH₂; nmr (CDCl₃/DMSO-d₆), 3.85 (s, OCH₃), 4.70 (s, CH₂-C=O), 6.58 (s, vinyl), 7.15–7.67 (m, ArH), and 8.15 (s broad, OH). Compd. 3: ir, 3101 (broad, OH), 1693 (C=O-O), and 1682 (C=O-CH₂); nmr (DMSO-d₆), 4.90 (s, CH₂-C=O) and 7.13 - 8.27 (m, ArH). Compd. 4: ir, 3174 (OH), 1726 (C=O-O), and 1651 (C=O-CH₂); nmr (DMSO-d₆), 4.70 (s, CH₂-C=O) and 6.73–8.20 (m, ArH, vinyl - enol, COOH). Compd. 5: ir, 1689 and 1681 (C=O-O and C=O-CH₂); nmr (CDCl₃), 4.63 (s, CH₂-C=O) and 7.10–8.27 (m, ArH and COOH). Comp. 6: ir, 1691 (shoulders, C=O-O and C=O-CH₂); nmr (CDCl₃/DMSO-d₆), 1.37 (s, Ar-C(CH₃)₃), 4.68 (s, CH₂-C=O₂), and 7.07 - 8.33 (m, ArH and COOH). Compd. 7: ir, 1674 (shoulders, C=O-O and C=O-CH₂); nmr (CDCl₃/MSO-d₆), 3.87 and 3.90 (s, ArOCH₃), 4.70 (s, CH₂-C=O), and 6.18–8.18 (m, ArH, vinyl - enol, COOH). Compd. 8: ir, 1684 and 1645 (shoulders, C=O-O and C=O-CH₂); nmr (CDCl₃/DMSO-d₆), 4.78 (s, CH₂-C=O₂) and 6.83 - 8.30 (m, ArH and COOH). Compd. 9: ir, 1700 (C=O-O); nmr (CDCl₃/DMSO-d₆), 3.92 and 3.95 (s, ArOCH₃), 7.40 - 8.33 (m, ArH), and 8.68 (s, COOH - exchange with D₂O). Compd. 10: ir, 3438 (OH), 1693 (C=O-O), and 1666 (C=O-CH₂); nmr (CDCl₃/DMSO-d₆), 3.93 (s, ArOCH₃), 4.62 (s, CH₂-C=O), and 6.93 - 8.18 (m, ArH and COOH). Compd. 11: ir, 1734 (C=O); nmr (DMSO-d₆), 3.92 (s broad, ArOCH₃) and 7.23 - 8.42 (m, C₄-H and ArH). Compd. 12: ir, 1724 (C=O); nmr (CDCl₃), 3.95 (s, ArOCH₃), and 6.82–8.40 (m, C₄H and ArH). Compd. 13: ir, 1644 (C=O-N); nmr (CDCl₃), 3.65 (s, N-CH₃), 3.85 (s, ArOCH₃), 3.95 (s, -CH₂-), and 6.51 8.18 (m, ArH). Compd. 14: ir, 1635 (C=O-N); nmr (DMSO-d₆), 3.55 (s, N-CH₃), 4.22 (s, -CH₂-), and 6.77 -8.05(m, ArH).