[gaiety]

Hi,all
I am having a problem about bromination reaction.Attached please find the reation. I tried many conditions but all of them give a mixture of di-bromide, mono-bromide and ary-bromide. Moreover, the starting material was remaining. Considering the side prodcuts would generate, NBS,Br2 or CuBr2 was only used with 1-1.5 eq. Many solvents are also screeened, such as HOAc,CHCl3,CHCl4,DMF,MeOH,diethyl ether,even the mixed solvents.But gave messy TLC and low yield.As a result, I tried to treat the starting material with TMSCl and then bromize it with NBS or CuBr2, but it still gave a mixture of mono-bromide and di-bromide.
All the procedure and result drive me crazy!Anyone is experienced in this class of reaction?Any suggestion will be appreciated.

[xc]

Hello

First of all, I must say I'm not experienced in this reaction. But I've been looking some literature about this topic and I have two ideas that may be useful for you:

1. Using a tetraalkylammonium tribromide, which is in general a quite mild reagent so it may be more selective than the ones you tested. Here you have two papers were they use this kind of reagents in the presence of aryl rings:
J. Med. Chem. 2006, 49(7), 2222-2231
J. Org. Chem. 2002, 67(1), 169-176

2. Using a catalyst especific for the carbonyl group. Here you have a paper by jorgensen reporting a chiral imidazolidine catalyst for alpha-bromination:
Chem. Commun. 2005, 4821 - 4823

I hope it helps you

[gaiety]

Thanks for your suggestion. I will get the references and work on them.

[phil81]

You could also try LDA, then quench with Br2

[russellm72]

Hi,

I agree why don't you try making the enolate and quenching with a source or Br. You can try a few small scale reactions and quench with D2O and analyse by NMR. This will show if your enol formation is fruitful. I know it seems like a bit of work but hey it seems you have put plenty of effort into this allready.

Have you done a Beilstein or Scifinder search for similar substrates? This might give you some useful guidelines.

You could also perhaps make the hydrazone and react again with a source of Br..

You'll get there and think how chuffed you'll be when you do!!!!


Let us know the outcome

Cheers

R.

[Shaun]

Even better than brominating the enolate directly:

First make the TMS enol ether with LDA and TMS triflate.  Isolate that.  Now treat that with an electrophilic source of bromine (IE Br2).  TMS enol ethers are nucleophilic enough to react with Br2.

You can probably generate the TMS enol ether in situ at -78C and quench with Br2 and then warm to room temperature.

[phil81]

What's the advantage over direct bromination? Fewer side reactions?

[russellm72]

Hi,

I think he said direct bromination gave a variety of products. The advantage is if you make the silyl protected enol ether you can purify and analyse at this juncture. At least that way you can prove the first step (enol formation) is fruitful. Then you can use a variety of brominating reagents to yield the product. If however the enol ether is not accessible then the strong base method looks unrewarding.

Of course if the starting material is cheap and readily accessible then you may just have to take a hit on yield however frustrating it may be.

R

[Mitch]

Did you add less than 1 equivalent of Bromine necessary? Also, did you add the brominating agent slowly (perhaps by syringe pump) to make sure it likely only affords the mono-substituted bromine.