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Trimethylacetylation of Methyl Indole-3-Carboxylate; Methyl N-Trimethylacetylindole-3-carboxylate

SyntheticPage 880
DOI: 10.1039/SP880
Submitted Mar 18, 2019, published Apr 05, 2019
Andrew Schneerer (schne586@umn.edu), Jilan Kreibich (gkreibic@umn.edu), Wayland Noland (nolan001@umn.edu)
A contribution from Noland Group


			Reaction Scheme: Trimethylacetylation of Methyl Indole-3-Carboxylate

Chemicals Used

Methyl indole-3-carboxylate (99%, Aldrich)
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

Methyl indole-3-carboxylate (5.107 g, 29.15 mmol, 1 eq.) was dissolved in dichloromethane (100 ml) and 4-(N,N-dimethylamino)pyridine (0.698 g, 5.713 mmol, 0.2 eq.), triethylamine (11.9 ml, 85.38 mmol, 3.0 eq.) was added to the solution. The mixture was then stirred for 30 minutes. Trimethylacetyl chloride (4.90 ml, 39.8 mmol, 1.4 eq.) was then added and the mixture was stirred overnight. The mixture was washed with deionized water (2 x 20 ml). The organic phase was then dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (1:8 ethyl acetate:hexane on SiO2), giving white crystals (5.712 g, 76%).

Author's Comments

The reaction probably does not need to be run overnight but this was found to be convenient. TLC can be used to determine the actual end point of the reaction. When the reaction is complete, a white precipitate can be seen which is primarily triethylammonium chloride. This material dissolves in the aqueous layer during the workup.

Data

Rf = 0.41 (SiO2, 1:4 EtOAc-hexanes)

M.p. 108-109.5 °C

1H NMR (500 MHz, CDCl3) δ 8.48 (d, J = 8.3, 1H), 8.42 (s, 1H), 8.18-8.16 (m, 1H), 7.42-7.37 (m, 2H), 3.97 (s, 3H), 1.56 (s, 9H)

13C NMR (126 MHz, CDCl3) δ 177.2, 164.5, 137.1, 131.4, 126.3, 125.8, 124.6, 121.2, 117.0, 112.8, 51.5, 41.6, 28.6

IR (film, cm-1) 3054.5, 2986.6, 2953.0, 1706.4, 1583.5, 1559.2, 1478.1, 1448.7, 1382.2, 1352.2, 1319.1, 1265.4, 1204.1, 1151.8, 1105.5, 1047.4, 898.7, 739.1, 704.7 cm-1

MS (EI, m/z)  [M]+ calculated for C15H17N1O3+ 259.1203, found 259.1202

Anal. Calcd for C15H17N1O3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.61; H, 6.68; N, 5.40


Lead Reference

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

Supplementary Information

Elemental Analysis (AKS-4-161f1 EA.tif)
IR (Methyl N-Pivindole-3-carboxylate IR.jpg)
1H NNR (Methyl N-Pivaloylindole-3-Carboxylate H NMR AKS-4-161.pdf)
13C NMR (Methyl N-Pivaloylindole-3-Carboxylate C NMR AKS-4-161.pdf)
GCMS (AKS-4-161f1 GCMS Methyl N-pivindole-3-carboxylate.jpg)
IR (Methyl N-Pivindole-3-carboxylate IR.jpg)

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Keywords: amides, aromatics/arenes, esters, indoles, trimethylacetylation

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