Synthesis of 2-methyltryptamine

As some people probably noticed, I like OPRD (Organic Process Research & Development), of course chemically speaking nothing weird, only classic chemistry but scalable synthesis and no COLUMN, for me the dream.
And sometimes we can find very interesting stuff, as this synthesis of the 2-methyltryptamine by the Grandberg methodology, which is indeed a modified Fisher indole synthesis.
This chemistry starts with the formation of the hydrazone between the phenylhydrazine and the 5-chloropentan-2-one, after cyclization and isomerization from iminium to enamine form, the rearrangment takes place to afford the tricyclic intermediates, which after loss of a proton provides the 2-methyltryptamine with 42% in almost 20 Kg scale!!!!! in A 800L reactor!!!!!!!!!!





Optimization and Scale-Up of the Grandberg Synthesis of 2-Methyltryptamine
Joel Slade, David Parker, Michael Girgis, Raeann Wu, Scott Joseph, and Oljan Repi
OPRD, 2007

Synthesis of 7-Prenylindole

I have seen some days ago this publication from M. Pirrung concerning the synthesis of 7-Prenylindole starting from indoline. This molecule is key ring in many natural products. As depicted below, the synthesis starts with copper catalyzed N-alkylation of indoline with 2-chloro- 2-methylbut-3-yne in THF in 91% yield on 10 mmol scale. After the reduction of the CC triple bound in alkene, the dimethylallylindoline obtained is submitted to a micro-wave assisted aza-claisen rearrangement in 90% yield (this step has been performed in a monomode micro-wave oven in a sealed tube at 150°C). Finally, the indoline has been oxidized into indole with MnO2 in DCM in 88% Yield.



I like this synthesis first, of course because this is indole ring, but also because the author uses one of my favorite reaction, the aza-claisen rearrangement, and my favorite tool for organic synthesis, a micro-wave oven.

Practical Synthesis of 7-Prenylindole
Xin Xiong and Michael C. Pirrung
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jo070734v

For the application of the 7-Prenylindole from the same author see:

Glyceraldehyde 3-Phosphate Dehydrogenase Is a Cellular Target of the Insulin Mimic Demethylasterriquinone B1
Hyunsoo Kim, Liu Deng, Xin Xiong, William D. Hunter, Melissa C. Long, and Michael C. Pirrung
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jm070437i

Synthesis of 2,3-substituted indole

For this come back, I propose you a titanium mediated synthesis of indole (intramolecular McMurry reaction) described some years ago by A. Fürstner starting from disubstituted aromatic rings, ketones in one hand and carboxamides in the other hand. The reaction is conducted in DME (dimethoxyethane) with TiCl3 and Zinc dust to provide different indole ring with good yield.

Organic Syntheses, Coll. Vol. 10, p.382 (2004); Vol. 76, p.142 (1999).