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SYNTHESIS OF DIMETHYLTRYPTAMINE (DMT)

BY ALKYLATION OF INDOLE GRIGNARDS WITH 2-(DIMETHYLAMINO)-ETHYL CHLORIDE

CHEMISTRY AND INDUSTRY 1388-89 (1964)

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The reaction of indolylmagnesium iodide with substituted alkyl halides, e.g., the nitriles Cl(CH2)nCN and chloroacetyl
diethylamide, to give the corresponding 3-substituted indoles is well established 112 although very reactive halides,
such as methyl iodide and benzyl chloride, occasionally give 1,3-disubstituted indoles3 . We report now that
indolylmagnesium iodide is alkylated by [3-dimethylaminoethyl chloride to afford N,N-dimethyltryptamine4 . The
method appears to be general and, although the reaction conditions are critical, it provides a convenient direct
synthesis of substituted tryptamines.

The indolylmagnesium iodide reagent was prepared in the usual manner2 from an indole and ethylmagnesium iodide
in dry anisole at 10°C. The mixture was cooled to -S°C and a solution of 2-molar equivalents of [3-
dimethylaminoethyl chloride in dry benzene was added. After 8 hours at -S°C the mixture was allowed to warm
slowly to room temperature, left overnight, and then added to aqueous ammonium chloride. The product was
obtained via extraction into dilute hydrochloric acid and subsequent neutralisation.

EtMgl
PhH, -5"C, Sh

Indole, 2-methylindole and 2-phenylindole afforded respectively, 2S, 30 and 1S% conversion into the corresponding
dimethyltryptamines. These were identified by elemental analysis and comparison of infrared spectra and mp with
authentic materials 516 . In each case the crude basic product was subjected to thin layer chromatography and no
other substituted indoles were detected.

Alternative conditions were investigated for the reaction with 2-phenylindole. We found that, in anisole, a higher
temperature decreased the yield (e.g., only 3% conversion at 40°C) and no alkylated products were obtained from
reactions in tetrahydrofuran or in ether, either in the cold or upon heating.

The C-alkylation of indolylmagnesium iodide is particularly interesting in comparison with other metal indole
derivatives. We found that 2-phenylindolyl sodium prepared from the indole and sod ium hydride, did not react with
[3-dimethylaminoethyl chloride in anisole at -S°C, but at a higher temperature N-alkylation occurred 7 and after 4
hours at 80°C 1-dimethylaminoethyl-2-phenylindole was obtained in 70% conversion. The latter, which has not
previously been reported, was recrystallised from light petroleum to give needles having mp 64-66°C (hydrochloride,
needles, mp 223-224.S 0 C). Similar results were obtained in tetrahydrofuran or dimethylformamide and in no case
could the C-alkylated product be detected.

The lithium derivative of 2- phenylindole was prepared by exchange with butyl lit hium in benzene, anisole was t hen
added and most of the benzene was removed by distillation. The reaction with [3-dimethylaminoethyl chloride for 4
hours at 84°C gave the N alkylated product in 23% conversion while at -S°C for 8 hours less than 1% conversion
was effected. In neither case was there evidence of C-alkylation.

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The contrast between N-alkylation of the indolylsodium and c-alkylation of the indolylmagnesium derivatives is
interesting and the reduced nucleophilicity of the indolic nitrogen of the magnesyl compound indicates that the
nitrogen is shielded from attack or is stabilised by co-ordination. If indolylmagnesium and indolylsodium are
essentially similar ionic species, as has been suggested by Reinecke et al. 8, our results imply that, at least in
anisole, the indolylmagnesium complex is not dissociated. If the magnesium is associated with the indolic nitrogen
then co-ordination of the solvent to magnesium could provide effective shielding and so prevent N-alkylation.
Interpretation is complicated by the solvent effect whereby the reaction has been favoured by anisole, the less basic
ether.

Further discussion of the mechanism is limited by the possibility that at least two alkylating species may be present.
For instance there is good evidence9 to support the view that 13-dimethylaminoethyl chloride, though formally an
alkyl halide, usually reacts with nucleophiles via the dimethylethylene-immonium ion. The alkylation of
indolylmagnesium at -5°C, but not at higher temperatures, certainly implies a competing reaction.

REFERENCES

1. Hoshino, T. & Tamura, K., Ann. Chem 500, 42 (1933);

Wieland, H., Konz, W. & Mittasch, H., Ann. Chem. 513, 1 (1934);
Binder, H. & Wegler, R., Arch. Pharm., 275, 506 (1937);
Nametkin, S. S., Dzbanovskii, N. A. & Rudnev, A. G., Compt. Rend. Acad. Sci. U.S.S.R., 32, 333 {1941)
2. Majima, R. & Hoshino, T., Ber. SBB, 2042 (1925); Williamson, W. R. N., J. Chem. Soc. 2834 (1962)
3. e.g. Hoshino, T. Ann. Chem. 500, 35 (1933)
4. The preparation of tryptamine from indolylmagnesium bromide and ethylene imine has been reported by
Bucourt, R. & Vignau, M., Bull. Soc. Chim. France 1190 (1961)
5. Hoshino, T. & Shimodaira, K., Ann. Chem. 520, 19 {1935)
6. Ames, A. F., Ames, D. E., Coyne, C. R., Grey, T. F., Lockhart, 1. M. & Ralph, R. S., J. Chem. Soc. 3388 (1959)
7. cf. Wright, J. B., J. Amer. Chem. Soc. 71, 1028 (1949)
8. Reinecke, M. G., Johnson, H. W. & Sebastian, J. F., Tetrahedron Letters 18, 1183 (1963)
9. Bartlett, P. D., Ross, S. D. & Swain, C. G., J. Amer. Chem. Soc., 71, 1415 (1949); Schultz, E. M. & Sprague, J. M.,
J. Amer. Chem. Soc., 70, 48 (1948) and references cited therein

NMR STUDY OF SOME ORGANOMETALLIC INDOLE DERIVATIVES

J. 0RG. CHEM. 36(21), 3091-95 (1971)

INDOLYLMAGNESIUM BROMIDE

To 1.2 g of magnesium (99.99%), in 15 ml of dry THF, was slowly added 5.2 g of ethyl bromide in 10 ml of THF,
without cooling but with vigorous stirring. After the reaction was completed 5.0 g of indole in 30 ml of dry THF was
added. The liberated ethane was measured in an inverted graduated cylinder filled with water. The theoretical
amount of ethane was collected in all cases. The indole Grignard reagent was completely soluble in THF.

INDOLYLLITHIUM

Indolyllithium was prepared by adding 5.0 g of indole in 15 ml of THF to a refluxing mixture of 0.35 g of lithium
hydride in 45 ml of THF. The resulting mixture was refluxed for 10-15 hr. The indolyllithium thus formed appeared to
be quite soluble.

INDOLYLSODIUM

A solution of 5.0 g of indole in 20 ml of dry THF was added to a mixture of 1 g of sodium hydride in 40 ml of
refluxing THF. The mixture was heated under reflux for another 30-60 min.

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