The Preparation of Substituted 1(2H)-Isoquinolinones from Polylithiated 2-(2-Methylphenyl)Hydrazinecarboxylic Acid Esters

Abstract

2-(2-Methylphenyl)hydrazinecarboxylic acid esters were metalated 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

(a) We found Schotten-Baumann condensation procedures of aromatic carboxylic acid chlorides too general. In order to avoid excess diacylation and still be able to make the entry compound expediently, we used a procedure that gave the desired entry compounds in 50 - 70% yield.

We noted the following resonance absortions for these products, which were not starting materials: ¹H nmr (CDCl₃), δ 2.47 and 2.60 ppm (ArCH₃). The spectra indicated that metalation of the ortho methyl hydrogens had not occurred.

Infrared spectra were obtained from a Mattson Polaris FT-Infrared Spectrometer. ¹H nmr 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. from Table, ir (paraffin oil), cm⁻¹; nmr (solvent);] Compd. 1; ir, 3379 (OH), 3313 (NH), 1721 (C=O), and 1646 (N-C=O); nmr (DMSO-d₆) δ 1.17 (t, CH₃), 4.11 (q, -OCH₂-), 6.68 (s, C₄-H), 6.77 - 7.88 and 8.20 - 8.43 (m, ArH), and 10.30 (s, broad, ArOH). Compd. 2; ir, 3426 (OH), 3239 (NH), 1722 (C=O), and 1653 (N-C=O); nmr (DMSO-d₆) δ 3.68 (s, OCH₃), 6.63 (s, C₄-H), and 6.78 - 7.88 and 8.13 - 8.45 (m, ArH). Compd. 3; ir, 3354 (OH), 3212 (NH), 1745 (C=O), and 1638 (Ar and N-C=O); nmr (DMSO-d₆/ CDCl₃), δ 1.40 (s, -OC(CH₃)₃), 6.48 (s, C₄-H), 6.70–8.55 (m, ArH). Compd. 4; ir, 3179 (NH), 1749 (C=O), 1648 (Ar and N-C=O); nmr (CDCl₃) δ 1.10 (t, CH₃-), 2.38 (s, ArCH₃), 4.10 (q, -OCH₂-), 6.50 (s, C₄-H), 7.13 - 7.73 and 8.30 - 8.53 (m, ArH). Compd. 5; ir, 3250 (NH), 1720 (C=O), and 1681 (Ar and N-C=O); nmr (CDC1₃) δ 1.15 (t, CH₃-), 1.33 (s, Ar-C(CH₃)₃), 4.16 (q, -OCH₂-), 6.52 (s, C₄-H), and 7.25 - 7.77 and 8.33 - 8.58 (m, ArH). Compd. 6; ir, 3180 (NH), 1746 (C=O), 1652 (Ar and N-C=O); nmr (CDCl₃) δ 1.38 (s, -OC(CH₃)₃), 6.53 (s, C₄-H), and 7.22 - 7.88 and 8.35 - 8.65 (m, ArH). Compd. 7; ir, 3265 (NH), 1726 (C=O), and 1687 (Ar and N-C=O); nmr (CDCl₃) δ 1.37 (s, ArC(CH₃)₃), 6.55 (s, C₄-H), 3.72 (s, OCH₃), and 7.28 - 7.88 and 8.33 - 8.63 (m, ArH). Compd. 8; ir, 3174 (NH), 1747 (C=O), and 1648 (Ar and N-C=O); nmr (CDCl₃) δ 1.42 (s, -OC(CH₃)₃), 6.52 (s, C₄-H), and 7.23 - 7.78 and 8.40 - 8.63 (m, ArH). Compd. 9; ir, 3218 (NH), 1744 (C=O), and 1668 (Ar and N-C=O); nmr (CDCl₃) δ 1.13 (t, CH₃-), 4.14 (q, -OCH2-), 6.52 (s, C₄-H), and 7.33 - 7.87 and 8.33 - 8.55 (m ArH). Compd. 10; ir, 3171 (NH), 1742 (C=O), 1643 (Ar and N-C=O); nmr (DMSO-d₆) δ 1.35 (s, -OC(CH₃)3), 3.80 (s, -OCH₃), 6.63 (s, C₄-H), and 6.90 - 7.88 and 8.13 - 8.45 (m, ArH). Compd. 11; ir, 3176 (NH), 1749 (C=O), 1653 (Ar and N-C=O); nmr (CDCl₃) δ 1.20 (t, CH₃-), 4.16 (q, -OCH₂-), 3.88 and 3.92 (s, ArOCH₃), 6.53 (s, C₄-H), and 7.43 - 7.87 and 8.30 - 8.63 (m, ArH). Compd. 12; ir, 3288 (NH), 1745 (C=O), and 1670 (N-C=O) cm⁻¹; nmr (CDCl₃) δ 1.42 (s, -OC(CH₃)₃), 3.88 and 3.90 (s, ArOCH₃), 6.53 (s, C₄-H), and 6.77 - 7.80 and 8.37 - 8.57 (m, ArH). Compd. 13; ir, 3178 (NH), 1726 (C=O), and 1681 (Ar and N-C=O); nmr (CDC1₃) δ 3.70 (s, OCH₃), 6.55 (s-br, CH=C, enol), and 7.17 - 7.77 and 8.37 - 8.57 (m, ArH). Compd. 14; ir, 3242 broad (NH), 1737 (C=O-O), and 1662 cm⁻¹ (C=O-N and Ar); nmr (DMSO-d₆) δ 2.28 (s, ArCH₃), 3.65 (s, -OCH₃), and 7.18 - 7.55 (m, ArH). Compd. 15; ir, 3321 and 3233 (NH), 1732 (C=O-O), and 1663 (C=O-N and Ar); nmr (CDCl₃/DMSO-d₆) δ 1.25 (t, -CH₃), 2.42 (s, ArCH₃), 4.16 (q, -OCH₂-), and 7.13 - 7.68 (m, ArH). Compd 16; ir, 3330 and 3244 (NH), 1722 (C=O-O), and 1660 (C=O-N and Ar); nmr (CDCl₃) δ 1.43 (s, -OC(CH₃)₃), 2.43 (s, ArH) and 7.12 - 7.68 (m, ArH).

Microanalysis for C, H, and N were performed by Quantitative Technologies, Inc., P.O. Box 470, Salem Industrial Park, Bldg. 5, Whitehouse, NJ 08888 and Robertsons Laboratory, 8 Samson Avenue, Madison, NJ 07940. [Compd. No. from Table] Calcd. for 1: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.90; H, 5.13; N, 8.37. Calcd. for 2: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.74; H, 4.80; N, 8.74. Calcd. for 3: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.16; H, 5.79; N, 7.96 Calcd. for 4: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.49; H, 5.65; N, 8.65. Calcd. for 5: C, 72.51; H, 6.64; N, 7.69. Found: C, 72.54; H, 6.50; N, 7.69. Calcd. for 6: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.40; H, 6.05; H, 8.25. Calcd. for 7: C, 71.98; H, 6.33; N, 7.99. Found: C, 72.04; H, 6.47; N, 7.88. Calcd. for 8: C, 64.78; H, 5.16; N, 7.55. Found: C, 664.93; H, 5.13; N, 7.58. Calcd. for 9: C, 63.07; H, 4.41; N, 8.17. Found: C, 63.15; H, 4.55; N, 8.07. Calcd. for 10: C, 68.84; H, 6.05; N, 7.64. Found: C, 68.88; H, 6.09; N, 7.56. Calcd. for 11: C, 63.31; H, 5.57; N, 7.03. Found: C, 63.22; H, 5.74; N, 6.88. Calcd. for 12: C, 64.78; H, 6.14; N, 6.57. Found: C, 64.69; H, 6.21; N, 6.66. Calcd. for 13: C, 65.38; H, 5.16; N, 8.96. Found: C, 65.34; H, 5.28; N, 8.85. Calcd. for 14: C, 57.69; H, 5.81; N, 13.45. Found: C, 57.77; H, 5.86; N, 13.49. Calcd. for 15: C, 59.45; H, 6.35; N, 12.60. Found: C, 59.38; H, 6.44; N, 12.46. Calcd. for 16: C, 62.38; H, 7.25; N, 11.19. Found: C, 62.43; H, 6.99; N, 11.19.

There are numerous reports concerning the preparation of 2,3-benzodiazepin-1-ones, and in each case the double bond is between N-3 and C-4, and not between C-4 and C-5. The latter location of the double bond would be in the 2,3-benzodiazepin-1-ones, if formed during the cyclization, prior to rearrangement to the 1(2H)-isoquinolinone

Initially 95% ethanol was used. If crystals did not form in several hours or overnight (refrigerator), a few drops of water or a few ice crystals were added.

A 1.6 M solution in hexanes was obtained from Aldrich Chemical Co. This material is satisfactory enough to effect metalation and dilute enough to permit expedient and safe handling.