Bromination w/NBS

[phenyl]

Have read about a lot of bromination methods but was wondering if anyone had ever, or if it is possible, to brominate 2c-h with NBS.  Any ideas are helpfull. Thanks.

[phenyl]

Sorry about this post, just found a lot of references with perchloric acid.  How about the conversion of 3,4-dimethoxy-pea to 3,4,5-trimethoxy-pea?

[Rhodium]

That is hard to do using conventional methods, as electrophilic substitution (such as bromination) of 3,4-dimethoxy-whatever produces 2-substituent-4,5-dimethoxy-whatever, and not 3,4-dimethoxy-5-substituent-whatever.

Was that understandable, or should I express myself more clearly?

[phenyl]

No, your post makes plenty of sense.  So bromination  makes 3,4-dimethoxy-2-bromo... and treat that with sodium methoxide for tma-2.  would this scheme have adverse reactions with a primary amine?

[Chromic]

You can't use NaOMe to do a williamson ether synthesis on an aromatic halide, this sort of chemistry can only be done with alkyl halides. To make your 2,4,5- trimethoxy you're going to have to form the phenol from the bromide made with NBS, deprotonate it, then methylate with dimethyl sulfate, methyl iodide, etc.

Read

https://www.thevespiary.org/rhodium/Rhodium/chemistry/345-tmb.html

for the general idea.

[Aurelius]

Perhaps you could just form the sodium or potassium salt of the phenol and react it with an alkyl halide (say methyl chloride)  to give the methoxylated compound.  (look at the reaction mechanism for forming safrole from DCM/base.   same thing but with two halogens and two phenolic positions.  and it only forms the ring b/c they are ortho positions. otherwise you'd get a haloalkoxy compound.

[foxy2]

Look here for a possible improved procedure

Post 287645

(foxy2: "3,4-Dihydroxy-5-methoxybenzaldehyde", Chemistry Discourse)
Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[Rhodium]

Chromic: Copper catalyzed substitution of aromatic halides with methoxide are indeed possible.

See this reference for example:

https://www.thevespiary.org/rhodium/Rhodium/pdf/arylhalide.methanolysis.cu-etoac.pdf

[uemura]

Chromic (and Rhodium)
nothing against the Chief bee's recommendations, but Uemura may recommend also to you to read the 'Vanillin' thread (see

Post 274828

(Natrix: "Vanillin", Chemistry Discourse)). Perhaps it helps to avoid some frustration.  

BTW: are there any succesful reports on copper based methoxylation of arylhalides without DMF around in the Hive? Uemura would bee realy interested in!
Carpe Diem

[Rhodium]

The reference above uses no DMF, and it works really great. Just make sure you have pure NaOMe.

[slappy]

I have done this multiple times. Just use 1 eq. N-Bromosuccinimide or 0.5 eq. 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) in Acetonitrile (or THF). Stir for 4-12h at room temp. Yields are >90%.

I would never, ever use Br₂ again. I hate that shit. I use NBS or DBDMH for any bromination that I can. If you have an unreactive substrate (not the case with 2C-H which is electron rich) just add 0.2 eq. Trimethylsilyltrifluoromethanesulphonate (TMSOTf). For very unreactive substrates (e.g. NO₂ or CF₃, etc) use 1.5 eq. in neat conc. H₂SO₄ and Trifluoroacetic Acid 4:1.

[phenyl]

Slappy, do you use perchloric acid as a catalyst when brominating 2c-h with nbs?  some details or references would be good. thanks.

[yellium]

How do you get rid of the reacted succinimide?

[Rhodium]

A simple water wash or an A/B extraction works. Succinimide is insoluble in organics and highly soluble in water.

[slappy]

There is no need to use Perchloric Acid as a catalyst. Just do it like I said and it will work. 1-1.1 eq. NBS (DBDMH works better sometimes) in MeCN, stir at R.T. for 12 hours. Partition between DCM and water, and a couple successive water washes to remove the succinimide.

I don't have my references handy right now, but I can assure you that this precedure works.

Note: Make sure to recrystallize the NBS from boiling water immediatly before use. When you get your NBS, it will be a yellow powder that smells of bromine. After recrystallization, you will get glistening white plates. Dry these, weigh, and add to reaction.

[Rhodium]

Slappy: Does this work as good with N-Chloro or N-Iodo-succinimide?

[slappy]

The order of reactivity in this case is NIS > NBS >> NCS. N-Iodosuccinimide is slightly more reactive than N-Bromosuccinimide, but N-Chlorosuccinimide is many folds less reactive. While you can Brominate to >90% by stirring at room temp for 4 hours, you would have to reflux for 4 days to Chlorinate with NCS. This has to do with the amount of the free electrophilic halide (X⁺) available, which is going to be lower as bond energies increase (N-Cl > N-Br > N-I).

[foxy2]

sulfuryl chloride sounds like the way to go for chloro.
From the ref on Rhods page
Those who give up essential liberties for temporary safety deserve neither liberty nor safety

[Rhodium]

I was mostly looking for a nice way of iodinating 1,4-dimethoxybenzene, which after reflux with sodium trifluoroacetate in NMP gives the 2,5-dimethoxy-trifluoromethylbenzene, which is further processed to 2C-TFM. Either that, or iodinating N-trifluoroacetyl-protected 2C-H, trifluoromethylate as above and deprotect.

I am hugely interested in fluorinated phenethylamines of all sorts, I would like that to be my doctoral dissertation.

[slappy]

Hehe. Great minds think alike, huh? You must be talking about the J. Chem. Soc., Perkins Trans paper from 1988. There is also a paper in Chem. Berichte 1996. I have done this too, with aromatic Bromides. The JCS paper uses NMP, while the Chem. Ber. paper uses DMF, with Sodium Trifluoroacetate and CuI.

The largest problem with this reaction is keeping it dry. Both Sodium Trifluoroacetate and Copper^I Iodide are extremely hydroscopic, and of course DMF and NMP just love water. When it gets wet, your yields go to shit.

[Rhodium]

Oh, I was thinking of Chemistry Letters, pp. 1719-20 (1981):
Abstract

Regiospecific trifluoromethylation by substitution of the halogen in aromatic halides was achieved by the use of sodium trifluoroacetate and copper(I)iodide. The reaction proceeded smoothly in dipolar aprotic solvents in good to high yields.

Example

A mixture of iodobenzene (5mmol), sodium trifluoroacetate (20mmol), and copper(I)iodide (10mmol) in N-methylpyrrolidone (NMP) (40ml) was heated under argon atmosphere. Evolution of CO2 began at around 140°C. After 4h stirring at 160°C, work-up of the resulting mixture afforded trifluoromethylbenzene in 72% yield (GLC). The reaction can be carried out in glass apparatus under normal pressure.

Iodobenzene => Trifluoromethylbenzene (72%)
m-Bromotoluene => m-Trifluoromethyl-toluene (58%)
2-Bromopyridine => Trifluoromethylpyridine (41%)

Please give me your refs! Do you think it would be best to start with 1,4-dimethoxyiodobenzene or a protected 2C-I for best yields? I am not sure if vilsmeyer formylation (or dichloromethyl methyl ether/TiCl4 formylation) would proceed with good yields on a trifluoromethylated substrate.