4-hydroxy-3-tert-butylanisole (TCI)
Ninhydrin (Aldrich)
Acetic acid (Aldrich)
4-methylaniline (Aldrich)
NaOH 2M
HCl (conc.)

To a hot solution of ninhydrin (24 g, 0.14 mol) in acetic acid was added 4-hydroxy,3-tert­-butylanisole (24.3 g, 0.14 mol). The mixture was heated to reflux for 2.5 h and then allowed to cool to room temperature, affording yellow crystals which were recovered by suction (31.3 g, not dried).

The crystalline product was added to acetic acid, and 4-methylaniline (19.7 g, 0.184 mol) was added. The mixture was heated to reflux for 24 h, and then allowed to cool to room temperature before being poured into water (500 ml). An unpleasant sticky precipitate formed, and the mixture was stirred with an overhead stirrer for 18 h to break up the lumps. The solid material was recovered by suction filtration (no. 3 sinter), stirred with Et₂O for 15 min and then collected by suction filtration, yielding a yellow powder (33.5 g).

The product was added to a solution of NaOH (2M, ~100 ml), heated to reflux for 15 min, and then allowed to cool to room temperature. A white precipitate was removed by suction filtration and washed with water. The washings were combined with the yellow filtrate, and acidified with HCl (conc.). The resulting white precipitate was isolated by vacuum filtration, washed with cold water and recrystallized from EtOH/H₂O, giving the title compound as a fine white powder (8.75g, 28%)

This is a modified version of an earlier general protocol page 6

¹H NMR 400 MHz (CDCl₃): δ ppm 10.85 (br. s, 1H, COOH), 7.27, 7.12 (2 × d, ⁴J_HH = 2 Hz, 1H, ArH), 4.70 (br. S, 1H, OH), 3.74 (s, 3H, OCH₃), 1.37 (s, 9H, C(CH₃)₃)

¹³C{¹H} NMR 100 MHz (CDCl₃): δ ppm 175.0 (COOH), 156.9, 151.2 , 139.9 , 124.2 (Ar), 123.9, 108.8 (ArH), 55.7 (OCH₃), 35.1 (C(CH₃)₃), 29.3 (C(CH₃)₃)

EA: found (calc) C: 64.31 (64.27), H: 7.07 (7.19), N: 0.13 (0.00)

MS (ESI): m/z 223 (M+)

G. Schmitt, N. D. An, J. P. Poupelin, J. Vebrel and B. Laude, Synthesis-Stuttgart, 1984, 758-760. 10.1055/s-1984-30960