Halogenation of methoxybenzenes with N-halosuccinimide

JOC 58(11), 3072-3075 (1993)

Activated aromatic nuclei can easily be brominated or chlorinated using the corresponding N-halo-succinimide in CCl4 or petroleum ether with perchloric acid as catalyst. The regioselectivity is excellent, giving only para-halogenated product, and the yields vary from 70-98% depending on substrate.

Experimental

2C-B or 2C-C from 2C-H

To a suspension of 0.1 mol N-halosuccinimide (17.8g NBS or 13.4g NCS) in 50ml hexane (or petroleum ether) were added 18.1g of 2,5-dimethoxyphenethylamine (0.1 mol) and 0.14 ml 70% perchloric acid (1 mol%) and the mixture was stirred for 20h at room temperature (or until disappearance of starting material on TLC). Potassium carbonate (0.2g) was then added, the solids were filtered off and the solvent evaporated and the residue distilled in vacuo to give the product in about 80% yield.

See Pihkal for easy isolation procedures of the hydrochlorides of 2C-B and 2C-C.

[Yellium's voice:]

Small caveat: I haven't bioassayed my home-brew DOC yet, although I'm quite convinced it will be active. Noticed a little bit of an `energy surge' about 30-60 minutes after trying to xtalize DOC.HCl, and _very_ mild closed eye visuals the next evening (yup, doc is probably a long one :-).

Side note: I know that I'm a clumsy chemist, and I didn't want to inhale any doc (yeah, I know, it goes to your lungs anyway, but there's no need to aid it :-), so I had a small face mask w/filter (the kind painters use when they're airbrushing things). Don't know how effective it is, but it prevents any powder from getting in your face. I guess that other contamination I got was from not wearing gloves all the time. Guess that I shouldn't try to make acid :-)

Anyway, synthesis was straightforward: [from memory] 2,5-DMA was prepared using literature methods (pihkal, #54). Took 1.8 gr 2,5-DMA, added 50 ml hexane, added 1.35 gr NCS, then added 15 uL 65% perchloric acid (with a micropipette).

Adding the perchloric acid caused an immediate darkening at the spot were the perchloric acid was added. At the bottom of the 100 mL flask was a lot of brownish gunk (most likely 2,5-DMA), which did not get into solution. After 24h, TLC analysis indicated that a little bit of the 2,5-DMA had reacted. Adding 50 ml of DCM caused all the brown gunk to dissolve, and when everything was dissolved, whitish solids almost immediately fell out of solution (NBS). TCL analysis 20 hours later indicated that the reaction was not yet completely over, but that most (~90%) of the 2,5-DMA was gone.

Workup: Added 20 mg Na2CO3, added approximately 200 mL H2O /sodium sulfite, washed, separated organic layer, then basified water layer and washed tree times with 100 mL DCM. Added DCM to organic layer, removed solvent on rotavap to yield a brownish oil. Attempts to form xtals (using IPA/Et2O/HCl) from this oil were unsuccesful, so therefore all solvents were removed again (rotavap), the remaining 3 gr of brownish oil was dissolved in approx. 400 mL H2O, acidified, washed 2 times with DCM (which removed much of the color), basified, extracted 3 times with DCM. DCM fractions were combined, solvent evaporated, giving about two gram of a less brown oil. Dissolving this oil in a few mL of IPA, adding ~40 ml dry ether and then adding HCL-gassed Et2O again didn't give crystals; instead, some yellowish/brown semisolid/semi-oil formed. Put the whole thing in the freezer (-18¡ÆC), next day added more dry Et2O, next day formation of tiny crystals, three days later more crystals. Threw away solvent, harvested 1.2 gr of hard to isolate sticky gunk which solidified when put under vacuum was applied.

Any bees who'd like to experiment with this: skip the hexane, use DCM directly. (similar to brominating 1,4-dimethoxybenzenes). Reaction time is 24 hours at least (note: at 15-20¡ÆC, was in a cold room). Note that when doing the workup of the reaction, a large amount of the good stuff goes into the aqeous layer.

This is about as much details as I can remember :-)

As said before: I haven't bioassayed it yet, but I guess that end product is most likely doc, and not 2,5-dma (maybe that the doc is only 80% pure, but then I would need a whopping 3 mg instead of 2.4 mg...)

[1] JOC 58(11), 3072-3075 (1993)