The Preparation of Substituted 1(2H)-Isoquinolinones from Dilithiated 2-Methyl-N-arylbenzamides, 2-Methyl-N-(arylmethyl)-benzamides, or 2-Methylbenzoic Acid, 2,2-Dimethylhydrazide

Abstract

2-Methyl-N-arylbenzamides (N-aryl-ortho-toluamides), 2-methyl-N-(arylmethyl)-benzamides (substituted benzyl, N-benzyl-ortho-toluamides), or 2-methylbenzoic acid, 2,2-dimethylhydrazide (ortho-toluic acid, N,N-dimethylhydrazide), were dilithiated with excess lithium diisopropylamide, and the resulting polyanion-type intermediates were condensed with aromatic esters followed by acid cyclization to the 3-substituted-1(2H)-isoquinolinones (isocarbostyrils).

Notes

Infrared spectra were obtained from a Mattson Polaris FT-Infrared Spectrometer. ¹H NMR spectra were obtained from a Varian Associates, EM-360L Nuclear Magnetic Resonance Spectrometer, and chemical shifts are reported in δ ppm downfield from an internal tetramethylsilane (TMS) standard. Compound No.; ir (paraffin oil), cm⁻¹; nmr (solvent) δ ppm: Compd. 1; ir, 1653 (ArH and N-C=O); nmr (DMSO-d₆) 6.80 (s, C₄-H), 7.38 (s, C₆H₅), and 6.62 - 8.68 (m, ArH). Compd. 2; ir, 1653 (N-C=O and ArH); nmr (CDCl₃) 6.73 (s, C₄-H), and 7.03 - 8.00 and 8.43 - 8.97 (m, ArH). Compd. 3; ir, 1651 (Ar and C=O); nmr (CDCl₃) 3.70 (s, ArOCH₃), 3.74 (s, ArOCH₃), 6.61 (s, C₄-H), and 6.77 - 8.03 and 8.49 - 8.85 (m, ArH). Compd. 4; ir, 1655 (Ar and N-C=O); nmr (CDCl₃) 1.27 (s, Ar-C(CH₃)₃), 3.77 (s, ArOCH₃), 6.52 - 8.03 (m, C₄-H and ArH), and 8.45 - 8.93 (m, ArH). Compd. 5; ir, 1651 (Ar and N-C=O); nmr (CDCl₃ and DMSO-d₆) 2.35 (s, ArCH₃), 2.35 (s, ArCH₃), 3.85 (s, ArOCH₃), 6.73 (s, C₄-H), and 6.90 - 7.90 and 8.47 - 8.82 (m, ArH). Compd. 6; ir, 1660 (Ar and N-C=O); nmr (CDCl₃ and DMSO-d₆) 6.77 - 8.77 (m, C₄-H and ArH). Compd. 7; ir, 1664 (Ar and N-C=O); nmr (CDCl₃) 2.32 (s, ArCH₃), 5.28 (s, -CH₂-), 6.55 (s, C₄-H), 3.72 (s, ArOCH₃), and 7.28 - 7.88 and 8.33 - 8.63 (m, ArH). Compd. 8; ir, 1660 (Ar and N-C=O); nmr (CDCl₃) 2.28 (s, ArCH₃), 3.88 (s, ArOCH₃), 5.30 (s, -CH₂-), 6.53 (s, C₄-H), and 6.80 - 8.07 and 8.22 - 8.83 (m, ArH). Compd. 9; ir, 1647 (Ar and N-C=O); nmr (CDCl₃) 2.31 (s, ArCH₃), 5.28 (s, -CH₂-), 6.55 (s, C₄-H), and 6.82 - 7.89 and 8.59 - 8.88 (m, ArH). Compd. 10; ir, 1655 (Ar and N-C=O); nmr (CDCl₃ and DMSO-d₆) 5.33 (s, -CH₂-), and 6.62 - 8.68 (m, C₄-H and ArH). Compd. 11; ir, 1653 (Ar and N-C=O); nmr (CDCl₃ and DMSO-d₆) 3.90 (s, ArOCH₃), 5.37 (s, -CH₂-), 6.58 (s, C₄-H), and 6.92 - 8.03 and 8.60 - 8.87 (m, ArH). Compd. 12; ir, 1666 (sh) and 1645 (Ar and N-C=O); nmr (CDCl₃) 3.18 (s, -N(CH₃)₂), 6.60 (s, C₄-H), and 7.48 - 7.88 and 8.58 - 8.82 (m, ArH). Compd. 13; ir, 1655 (Ar and N-C=O); nmr (CDCl₃) 2.47 (s, ArCH₃), 3.02 (s, -N(CH₃)₂), 6.52 (s, C₄-H), and 7.30 - 8.70 (m, ArH). Compd. 14; ir, 1652 (N-C=O and ArH); nmr (DMSO-d₆) 3.07 (s, -N(CH₃)₂), 4.00 and 4.03 (s, ArOCH₃), 6.57 (s, C₄-H), and 7.00 - 8.77 (m, ArH). Compd. 15; ir, 1645 (N-C=O and Ar); nmr (CDCl₃) 3.03 (s, -N(CH₃)₂), 3.93 (s, ArOCH₃), 6.43 (s, C₄-H), and 6.88 - 7.90 and 8.30 - 8.63 (m, ArH). Compd. 16; ir, 3273 (NH) and 1633 (Ar and N-C=O); nmr (CDCl₃ and DMSO-d₆) 2.43 and 2.48 (s, ArCH₃), 4.63 (d, -CH₂-), and 7.27 - 7.60 (m, ArH).

Combustion analysis for C, H, and N were performed by Quantitative Technologies, Inc., P.O. Box 470, Salem Industrial Park, Bldg. 5, Whitehouse, NJ 08888. [Compd. No. from Table] Calcd. for 2: C, 76.02; H, 4.25; N, 4.22. Found: C, 75.88; H, 4.56; N, 4.02. Calcd. for 3: C, 77.29; H, 5.36; N, 3.92. Found: C, 77.00; H, 5.53; N, 3.85. Calcd. for 4: C, 81.43; H, 6.57; N, 3.65. Found: C, 81.16; H, 6.72; N, 3.57. Calcd. for 5: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.85; H, 5.74; N, 3.97. Calcd. for 6: C, 80.49; H, 4.82; N, 4.47. Found: C, 80.55; H, 4.78; N, 4.40. Calcd. for 7: C, 76.77; H, 5.04; N, 3.89. Found: C, 76.65; H, 5.43; N, 3.93. Calcd. for 8: C, 81.10; H, 5.95; N, 3.94. Found: C, 81.08; H, 6.11; N, 3.87. Calcd. for 9: C, 76.77; H, 5.04; N, 3.89. Found: C, 76.63; H, 5.38; N, 3.73. Calcd. for 10: C, 76.41; H, 4.66; N, 4.05. Found: C, 76.59; H, 4.88; N, 4.18. Calcd. for 11: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.59; H, 5.60; N, 4.12. Calcd. for 12: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.34; H, 6.23; N, 10.51. Calcd. for 13: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.60; H, 6.76; N, 9.82. Calcd. for 14: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.84; H, 6.26; N, 7.83. Calcd. for 15: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.54; H, 6.18; N, 9.48. Calcd. for 16: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.27; H, 7.03; N, 5.81.