Inspired by Post 518711 (https://www.thevespiary.org/talk/index.php?topic=13048.msg51871100#msg51871100)
(Lego: "DMT from indigo in two steps?", Tryptamine Chemistry) Lego searched the literature in order to evaluate if it is possible to alkylate indoles in the 3 position. This would offer a one-step synthesis of tryptamines directly from indoles.
The problem is the highly electron rich pyrrole ring. It can bee alkylated either at the 3-position (what we want), the 2-position (bad) and the 1-position (the nitrogen of the pyrrole, bad too). As the 3-position is the most activated position it should bee the prefered position of attack.
There are two imaginable ways of alkylating indoles, direct or with a catalyst (like a Friedel-Crafts alkylation).
The other choice is alkylating agent, it can bee either an alkyl halogenide or a alcohol.
Here are some examples of indole alkylations in the 3-position:
Heterocycles, 2001, 55(4), 653-660:
A mixture of DL-serine (1.20 g, 11.4 mmol) and acetic anhydride (2.4 mL, 23 mmol) in AcOH (7.0 mL) was heated for 1 h at 80 oC, and then 4-bromoindole (1.12 g, 5.70 mmol) was added to the solution. After being heated at 80 °C for 1.5 h, the reaction mixture was basified with 30% aqueous NaOH and washed three times with benzene-AcOEt (1 : 1). The aqueous layer was acidified with concentrated HCl and extracted three times with benzene-AcOEt (1 : 1). The organic layer was washed with brine and dried over MgSO4. After evaporation of the solvent, resulting crude amorphous solid (1.13 g) was subjected to chromatography over neutralized silica gel (benzene : AcOEt = 1 : 5 ~ 1 : 8) to give the acid {4-bromo-acetyl-tryptophan} (1.06 g, 57%) as a pale brown amorphous solid.
The authors prepared plenty of other substituted tryptophans with the same method (e.g. 7-bromo in 84% yield w/o chromatographic workup).
To avoid over-alkylation it is possible to use an excess of indole compared to alkylating agent or to block the 2-position e.g. by a carboxylic acid ester which can bee removed by decarboxylation, Post 531852 (missing)
(Lego: "Hemetsberger-Knittel: Benzaldehydes to Indoles", Tryptamine Chemistry).
J. Med. Chem., 1991, 34(4), 1283-1292:
2-Carboxy-3-indolepropanoic Acid: Ethyl 2-indolecarboxylate (3 g, 15.9 mmol), ethyl 3-iodopropanoate (5.4 g, 22.3 mmol), K2CO3 (5 g), and acetonitrile (50 mL) were combined and heated to reflux for 48 h. The mixture was poured into H2O (50 mL) and the aqueous mixture was extracted with ether (3 x 75 mL). The combined ether solutions were washed with H2O (3 x 30 mL), dried (Na2SO4), and concentrated in vacuo. The resulting crude diester was hyrolyzed to diacid (2.37 g, 64%) as described.
If no strong base is used the alkylation of pyrrole nitrogen is very unlikely, therefore it should bee possible to alkylate indoles with either N,N-dimethyl-2-aminoethanol (cheap and commercial available) with the first procedure or with 2-chloro-N,N-dimethylethylamine (also cheap and commercial available).
Please not that the reaction is different than this one: ../rhodium/chemistry
/dmt.indole.grignard.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry
/dmt.indole.grignard.html)
Lego remembers someone who was able to alkylate an excess of indole with a N-disubstituted 2-chloroethylamine in THF with ZnCl2 with very good yields and obtain the product by sublimation.
What do you think?
Please note that according to Post 519153 (missing)
(Vitus_Verdegast: "Monitored for reagents used in chem weapons", Law and Order) this compound is a watched precursor in the EU!
All N,N-dialkylated aminoethyl-2-chlorides or the corresponding ethanolamines are precursors for chemical warfare agents.
Bee careful!!!
According to Beilstein Crossfire:
Chemical Name: (2-chloro-ethyl)-diisopropyl-amine
(2-Chlor-aethyl)-diisopropyl-amin
2-chloro-N,N-diisopropylethylamine
Autoname: (2-chloro-ethyl)-diisopropyl-amine
CAS Registry Number: 96-79-7
Molecular Formula: C8H18ClN
Molecular Weight: 163.69
Melting Point:
118 - 1271 1
Ref. 1: Ortho Pharmaceutical Corp.; Patent US2949485 (http://l2.espacenet.com/dips/viewer?PN=US2949485&CY=gb&LG=en&DB=EPD)
; 1960; Chem.Abstr.; EN; 55; 1448e; 1961.
Boiling Point:
48 - 50°C (1 torr)1 1
66 - 67 (13 torr)2 1
Ref. 1: Vecchi; Melone; ANCRAI; Ann.Chim.(Rome); 49; 1959; 1192, 1203.
Ref. 2: Wright et al.; JACSAT; J.Amer.Chem.Soc.; 72; 1950; 3536,3537.
That article referenced above by Lego was really excellent. It
contained the preparation of ten different N,N-dialkylaminoethyl chlorides
as well as the corresponding N,N-dialkylaminoethanol precursors.
Histamine Antagonists. VII. Phenothiazine Derivatives
John B. Wright, Edward H. Lincoln, Richard V. Heinzelmann, James H. Hunter
J. Am. Chem. Soc. 72, 3536-3539 (1950)
(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/pdf.gif)