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Cyclo-alkylation of the primary amine of tryptophan methyl ester to a pyrrolidine; Methyl 3-(1H-indol-3-yl)-2-(pyrrolidin-1-yl)propanoate

SyntheticPage 831
Submitted Oct 02, 2017, published Oct 05, 2017
Andrew Schneerer (schne586@umn.edu), Nathaniel Olson (olso4006@umn.edu), Wayland Noland (nolan001@umn.edu)
A contribution from Noland Group


			Reaction Scheme: Cyclo-alkylation of the primary amine of tryptophan methyl ester to a pyrrolidine

Chemicals Used

Tryptophan methyl ester HCl
Potassium Bicarbonate (ACS grade, 99.7%; Mallinckrodt)
1,4-Dibromobutane (99%, Aldrich)
Acetonitrile (ACS grade, 99.9%; Fisher)

Procedure

Tryptophan methyl ester HCl (1.159 g, 3.783 mmol, 1 eq.) was suspended in acetonitrile (100 mL). Potassium bicarbonate (1.790 g, 17.87 mmol, 4 eq.) was added, followed by 1,4-dibromobutane (0.82 mL, 6.87 mmol, 1.5 eq). The mixture was then heated at reflux for 4 days after which the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (2 × 40 mL). The combined organic phases were dried over magnesium sulfate and the solvent was removed under reduced pressure, leaving a brown oil. The crude product was purified by column chromatography (1:10–1:1 ethyl acetate:hexane on basic Al2O3), giving a yellow oil (0.970 g, 78%).

Author's Comments

The level of dilution used in this experiment is necessary to prevent crosslinking of multiple tryptophan methyl ester molecules. If the volume of acetonitrile used is reduced the yield of product decreases.

Data

Rf = 0.31 (Al2O3, 1:2 hexane-ethyl acetate)
1H NMR (500 MHz, CD2Cl2): δ 8.137 (s, br., 1H), 7.582 (d, J = 7.9, 1H), 7.359 (dt, J = 8.0, 0.9, 1H), 7.160 (ddd, J = 8.3, 7.0, 1.2, 1H), 7.088 (ddd, J = 8.0, 7.0, 0.9, 1H), 7.047 (d, br., J = 2.2, 1H), 3.572–3.544 (m, 1H), 3.524 (s, 3H), 3.240–3.158 (m, 2H), 2.783–2.681 (m, 4H), 1.816–1.761 (m, 4H)
13C NMR (126 MHz, CD2Cl2) δ 173.06, 136.03, 127.32, 122.50, 121.82, 119.21, 118.55, 111.47, 111.08, 67.93, 51.30, 50.94, 27.28, 23.36
IR (KBr, cm-1) 3407, 3056, 2952, 2876, 2840, 1732, 1620, 1457, 1356, 1435, 1355, 1341, 1293, 1211, 1168, 1068, 1010, 741 cm-1
MS (EI, m/z) [M]+ calculated for C16H20N2O2+ 272.1519, found 272.1525

Lead Reference

Trejo Muñoz, C. R.; Mancilla Percino, T.; Mera Jiménez, E.; Correa-Basurto, J.; Trujillo-Ferrara, J. G. Med. Chem. Res. 2013, 22 (8), 4039–4045.

Supplementary Information

e.g. Actual NMR spectra (as images or jdx files for interactive spectra), photographs of apparatus, TLC’s or crystals or videos. Please contact the ChemSpider team (ChemSpider-at-rsc.org) for help with this.
HRMS (HRMS-EI.jpg)
1H NMR (Methyl 3-(1H-indol-3-yl)-2-(pyrrolidin-1-yl)propanoate.pdf)
13C NMR (Methyl 3-(Indol-3-yl)-2-(pyrrolidin-1-yl)propanoate C.pdf)
IR (Pyrrolidino Trypophan Methyl Ester IR.jpg)

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Get structure file (.cdx, .sk2, .mol)

Keywords: addition, alkyl/alkenyl/aryl halides, amination, amines, amino acids, heterocyclic compounds, indole, tryptophan

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