phenyl (Stranger)
03-25-02 23:19
No 287776
      Bromination w/NBS  Bookmark   

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.
03-25-02 23:24
No 287781
      Sorry about this post, just found a lot of ...  Bookmark   

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?
(Chief Bee)
03-26-02 00:32
No 287811
      3,4-dimethoxy to 3,4,5-trimethoxy  Bookmark   

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?
03-26-02 00:50
No 287819
      No, your post makes plenty of sense.  Bookmark   

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?
(Hive Addict)
03-26-02 01:57
No 287837
      Phenyl, close... but not quite  Bookmark   

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 ../rhodium/chemistry /345-tmb.html for the general idea.
(Hive Bee)
03-26-02 05:08
No 287915
      salts  Bookmark   

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. 
(Distinctive Doe)
03-26-02 07:20
No 287961
      halide to hydroxy  Bookmark   

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
(Chief Bee)
03-26-02 08:45
No 287999
      ArBr + NaOMe -> ArOMe + NaBr  Bookmark   

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

See this reference for example: ../rhodium/pdf /
(Hive Photographer)
03-27-02 10:43
No 288470
      Minor concern..  Bookmark   

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. smile

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
(Chief Bee)
03-27-02 13:25
No 288507
      No DMF  Bookmark   

The reference above uses no DMF, and it works really great. Just make sure you have pure NaOMe.
(Hive Bee)
03-27-02 21:07
No 288640
      Bromination  Bookmark   

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.
03-30-02 19:24
No 289912
      Slappy, do you use perchloric acid as a catalyst ...  Bookmark   

Slappy, do you use perchloric acid as a catalyst when brominating 2c-h with nbs?  some details or references would be good. thanks.
(Hive Addict)
03-30-02 21:17
No 289966
      How do you get rid of the reacted succinimide?  Bookmark   

How do you get rid of the reacted succinimide?
(Chief Bee)
03-31-02 00:14
No 290020
      Removing succinimide  Bookmark   

A simple water wash or an A/B extraction works. Succinimide is insoluble in organics and highly soluble in water.
(Hive Bee)
03-31-02 04:24
No 290106
      No HClO4 needed.  Bookmark   

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.
(Chief Bee)
03-31-02 05:57
No 290141
      NCS/NIS?  Bookmark   

Slappy: Does this work as good with N-Chloro or N-Iodo-succinimide?
(Hive Bee)
03-31-02 17:45
No 290385
      NCS << NBS < NIS  Bookmark   

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).
(Distinctive Doe)
03-31-02 18:03
No 290391
      sulfuryl chloride  Bookmark   

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
(Chief Bee)
03-31-02 18:04
No 290392
      Uses of NIS  Bookmark   

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.
(Hive Bee)
04-01-02 10:07
No 290800
      CF3  Bookmark   

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 CopperI Iodide are extremely hydroscopic, and of course DMF and NMP just love water. When it gets wet, your yields go to shit.
(Chief Bee)
04-01-02 19:24
No 290963
(Rated as: excellent)

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

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.


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 140C. After 4h stirring at 160C, 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.