MgO alkylation of indole

methylenedioxy · Sun Apr 03, 2005 9:30 pm

A great promising idea from:

Bengü Sezen and Dalibor Sames
Selective C-Arylation of Free (NH)-Heteroarenes via Catalytic C-H Bond Functionalization
J. AM. CHEM. SOC. 2003, 125, 5274-5275

The paper is free and you can download it. See also the supporting information in which there are important details.

The paper describes a method for 2-arylation of indole. The best base for this reaction is ? MgO. Indole reacts partially with MgO in THF ? AT ROOM TEMPERATURE ? to form an indole-MgOH Grignard-like salt. Quote from the supporting info:

In a flame dried flask, indole (50 mg, 0.427 mmol) and MgO (20.6 mg, 0.512 mmol, 1.2 equiv) were suspended in 1 ml of d8-THF and stirred at room temperature for 10 minutes to get a homogeneous suspension. The mixture was filtered through a medium porosity fritted funnel under argon and placed to a flame dried NMR tube. The resultant species was characterized by 1H and 13C NMR spectroscopy (see page S17 and S18). Later, the solvent was removed under vacuo and the residual salt was used to prepare KBr pellet for the IR analysis (see page S19). The data showed that the salt formation is incomplete providing a mixture of indole and the presumed indole magnesium hydroxide

Arylation with phenyliodide proceeds with the help of Pd/Cu catalysts at 150 deg in dioxane/DMF, and the aryl enters the 2-nd position. But the 3-rd position is activated too, since more hindered o-tolyliodide gives a considerable quantity of 3-substituted product.

Nobody here is interested in Pd-catallyzed arylations, but the paper is a rising hope for 3-alkylation of indole with simple MgO without all the tortures of preparing indole Grignargs. I have made some molecular mechanics calculation and they show that 2-arylindoles are more favorable than 3-substituted, but with alkyls the 3-product indeed is expected to be dominant. Direct alkylation with Me2NCH2CH2Cl is maybee impossible or very low yielding, but alkylation with dibromo- or dichloroethane will be enough to make a revolution in tryptamine synthesis.

I have no analytical facilities, so my supplication to all well equipped bees: mix indole, 1.2 eq. of MgO, and an excess of DCE in THF, dioxane, etc., and see what will happen.

IndoleAmine · Dreamreader Deluxe

Sounds good - but you probably will get 20% bis-(indol-3-yl) byproduct that way, better use ethyl bromide instead of DCE for example...

i_a

java · Consumer

methylenedioxy......In reading your post I found this article that may be of some assistance to your project.........java
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"The authors have also examined indole alkylations using this methodology. They have found that catalysts 5
and 7 promote indole alkylations in high yields and with good stereocontrol (Scheme 2).4"

.............as taken from "Enantioselective Organocatalysis: A Valuable Strategy for Asymmetric Synthesis"
David W. C. MacMillan (California Institute of Technology). found in this pdf by the Albany Molecular Research group

Note: highlighted in yellow in page 6 of pdf

methylenedioxy · Mon Apr 04, 2005 12:59 pm

I think this catalyzer is too exotic, but all reports of Albany Mol. Res. Groups are very interesting. They exist as html files too.

And, again, please, just mix THF, indole, MgO and some alkylhalogenide and see what will happen. I have even no TLC plates in the moment.

methylenedioxy · Fri Apr 08, 2005 1:22 pm

Crazy experiments lead to Nobel or to Nothing, said Erasmus Darwin (the uncle of his nephew Charles D.). Erasmus played trumpet before his tulips and nothing happened. I made something similar.
1.2 g of indole (~10 mmol), 1.5 g of Me2NCH2CH2Cl.HCl (~10 mmol), and 1 g of MgO (~25 mmol) were put in an agate ball mill. The weight of the balls was 120 g (balls:reactants = 30:1). After 1-2 hours the mixture aquired a nasty amine smell, and after 5 hours milling at 6000 rpm it became a grey goo which was impossible to mill. The goo was dissolved with ultrasound sonification in 100 ml DCM, filtered, to filtrate 100 ml dilute HCl was added (to extract the putative DMT), and the acid extract was alkalized with K2CO3 (to liberate the putative DMT). Nothing. No DMT, no amine.
Obviosly, a solvent is needed.

Lego · Wed Jul 06, 2005 2:02 am

methylenedioxy · Sun Jul 10, 2005 3:09 pm

Lego, I don't ask who told you this, but PLEASE give some more details. It sounds so good.

Lego · Sun Jul 10, 2005 4:03 pm

Sorry, if Lego could tell you more details she would but Lego does not know any further details. It works, at least with this secondary amine. Don't know the yields, but this is secondary if you consider the price of the chemicals. It is better to use an excess of indole in order to prevent 2,3-dialkylation, don't know anything about the yields, not too high, but enough for several bioassays.
Perhaps THF is not the best solvent as ZnCl₂ will cleave the ether bond, perhaps DCM works better?
Lego suggests to react the stuff, monitor it by TLC, then quench it with ice water, acidify the water phase, wash with NP to remove indole, basify, extract with NP, distill of the alkylating agent and purify the (hopefully formed) tryptamine.

Lego looked for a similiar reaction in many textbooks and searched SciFinder & Beilstein, most mention it not at all, some say C3-alkylation does work well without giving any details, so the whole reaction is an undiscovered territory for bees. In the last time there were several articles about C3-alkylation but not with alkylhalogenides but with a,b-unsaturated ketones and similiar reagents.

GOOD LUCK!

Lego · Mon Jul 11, 2005 12:54 am

Lego · Thu Sep 29, 2005 2:58 am

Now imagine N,N-dimethylserine or even N,N-dimethylaminoethanol.....

Convenient synthesis of 70 and 60-bromo-D-tryptophan and their derivatives by enzymatic optical resolution using D-aminoacylase
Yaeko Konda-Yamada, Chiharu Okada, Kiminari Yoshida, Yasuyuki Umeda, Shiho Arima, Noriko Sato, Toshitsugu Kai, Hiroaki Takayanagi and Yoshihiro Harigaya
Tetrahedron, 2002, 58(39), 7851-7862

N-Acetyl-7'-bromo-DL-tryptophan
L-Serine (1.06 g, 10.3 mmol) was dissolved in a solution of 7-bromoindole (1.00 g, 5.13 mmol) in AcOH (12.0 ml) and Ac2O (4.0 ml). After the solution was stirred at 758C for 2 h under argon, the mixture was diluted with diethyl ether (100 ml) and adjusted to pH 11 with 30% NaOH (40 ml). The water layer was further washed with diethyl ether (150 ml£3), then ice-cooled. The organic layer was further extracted with 1N NaOH (30 ml£2) and a small amount of Na2S2O4 was added to the combined alkali solution, which was then neutralized with conc. HCl, concentrated to 1/2 volume in vacuo to give precipitates, then acidified with 5% HCl to adjust to pH 3 using congo red as indicator, stored in refrigerator for 24 h. The resulted precipitates were collected by filtration and dried to give crystals. The filtrate was concentrated to 1/2

Lego · Thu Sep 29, 2005 4:13 am

Synthesis and evaluation of the antiovulatory activity of a variety of melatonin analogs
Michael E. Flaugh, Thomas A. Crowell, James A. Clemens, Barry D. Sawyer
J. Med. Chem., 1979, 22(1), 63-69

The more reactive indoles were alkylated at the 3 position by reaction with nitroethene generated in situ by thermolyyis of nitroethyl acetate

So, what about in situ generation of the enamine of acetaldehyde and dimethylamine by reacting dimethylaminoethanol with acetic anhydride and subsequent thermolysis?

5-Methoxy-3-(2-nitroethyl)indole(13a)
A mixture of 20 g (0.14 mol) of 5-methoxyindole, 20 g (0.15 mol) of 2-nitroethyl acetate, and 0.5 g of tert-butylcatechol in 100 mL of xylene was refluxed under nitrogen for 3 h. The xylene was evaporated from the dark mixture under reduced pressure, and the residue was chromatographed on a column of silica gel that was eluted with 2% EtOAc in C₆ H₆ . Crystallization of the product from benzene-hexane gave 20 g (67%) of 13

methylenedioxy · Sat Oct 01, 2005 2:54 am

Thanx, Lego. You are a precious source on indole alkylations. The idea can be checked simply with DMAE. And there are other possibilities: ethanolamine (which will form N-ethanol-acetamide), N-ethanol-phthalimide, N-ethanol-tosylamide, saccaride, etc., to increase the positive charge on N. In the end we will have tryptamine which is not so bad. For DMT a crasy idea is to try DMAE-N-oxide-acetate. I don't know if the latter exists, but if it is stable enough, then SO2 or everything else in the end will easily desoxidize it to the desired product.