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The Royal Society of Chemistry"

Trimethylacetylation of 3-Acetylindole

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Submitted: February 15, 2019, published: March 28, 2019

Authors

Andrew Schneerer (schne586@umn.edu)

Emilie Raberge (raber006@umn.edu)

Wayland Noland (nolan001@umn.edu)

A contribution from 

Reaction Scheme

Chemicals

3-Acetylindole (97%, Ark Pharm)
Dichloromethane (HPLC grade, 99.8%, Aldrich)
4-(N,N-dimethylamino)pyridine (HPLC grade, 99.9%, Chem-Impex)
Triethylamine (Reagent grade, 99%, Fischer)
Trimethylacetyl Chloride (98%, Beantown Chemical)

Procedure

3-Acetylindole (10.007 g, 63.262 mmol, 1 eq.), 4-(N,N-dimethylamino)pyridine (1.542 g, 12.62 mmol, 0.2 eq.) and triethylamine (26.3 mL, 188 mmol, 3 eq.) were dissolved in dichloromethane (500 mL) and stirred at room temperature for 30 minutes. Trimethylacetyl chloride (10.8 mL, 88.0 mmol, 1.4 eq.) was added and the solution was stirred at room temperature for 4 days. The reaction mixture was washed with water (1 x 100 ml) and dried over magnesium sulfate. The drying agent was filtered off and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (1:4 ethyl acetate:hexane on SiO2), giving white crystals (13.036 g. 86%).

Author Comments

The solution probably does not need to be stirred for 4 days. We usually have found that the reaction was not finished after 1 or 2 days, so a 4 day reaction time was used to be sure it was complete. TLC can be used to monitor reaction completion. Allowing the crude reaction mixture to stay in contact with silica for more than a few days does cause slow loss of the trimethylacetyl group. The solution was yellow when trimethylacetyl chloride was added, and slowly became dark red over a few hours. The product before column chromatographic purification was a yellow-orange solid.

Data

Rf = 0.17 (SiO2, 1:4 EtOAc:hexanes)

M.p. 118-120 °C

1H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 7.9, 1H), 8.35 (s, 1H), 8.34 (d, J = 6.4, 1H), 7.44-7.38 (m, 2H), 2.61 (s, 3H), 1.58 (s, 9H)

13C NMR (126 MHz, CDCl3) δ 193.5, 177.0, 137.3, 131.4, 126.12, 126.09, 125.0, 122.0, 121.1, 116.8, 41.6, 28.7, 27.9;

IR (film, cm-1) 3054.4, 2986.3, 1710.7, 1667.1, 1547.6, 1478.4, 1447.1, 1349.4, 1319.3, 1265.4, 1193.8, 1174.9, 1149.5, 1137.1, 1009.4, 897.5, 740.7, 705.0, 645.1 cm-1

MS (EI, m/z) [M]+ calculated for C15H17N1O2+ requires 243.1254, found 243.1252.

Anal. Calcd for C15H17N1O2: C, 74.05; H, 7.04; N, 5.76. Found: C, 74.18; H, 7.16; N, 5.76

Lead Reference

Hostier, Thomas; Ferey, Vincent; Ricci, Gino; Pardo, Domingo Gomez; Cossy, Janine.; Chem. Comm. 2015, vol. 51, # 73, 13898 - 13901

Keywords

amides, aromatics/arenes, indoles, ketones, trimethylacetylation