[quantumnumber]

Hi guys,
an easy one:
How could I carry out a bromination of a ketone on the less substitued side?
I know that bromination in acidic conditions will give the not-desired product... And no other simple way comes to my mind.

Thanks!

[quantumnumber]

I've thought this, trying to control the halogenation with an enolate equivalent, but I think there could still be problems with deprotonation of the most acidic hydrogen (the one next to the bromine), and so further halogenation... Maybe with stoichiometric control and low temperature would work.

[AromaticAcrobatic]

Quantum,
I don't think that last halogenation step would actually work. Starting with Butane, I would either add Br2 and UV light or NBS and heat. Then a big sterically hindered base to get almost all ( if not all of) the E2 Product and also the Hoffman product. Then from the Hoffman product add Br2, h20 and then A strong oxidizing agent like chromic acid to turn that secondary alcohol into the ketone. The final product would be your 1,-bromo-2,-butanone

[orgopete]

This looks like a product from a longer series of steps. If bromine and catalyst doesn't give bromination in the less substituted position, how was that accomplished in your class or textbook?

[quantumnumber]

This looks like a product from a longer series of steps. If bromine and catalyst doesn't give bromination in the less substituted position, how was that accomplished in your class or textbook?

I don't know really... Nowadays I'm preparing an exam about retrosynthetic analysis, so I was doing an excercise, trying to figure out how to get the target molecule, and I ended up needing this reagent (according to my plan of synthesis). I thougt this halo-ketone would be easy to prepare, but I realized it isn't.

[quantumnumber]

Quantum,
I don't think that last halogenation step would actually work. Starting with Butane, I would either add Br2 and UV light or NBS and heat. Then a big sterically hindered base to get almost all ( if not all of) the E2 Product and also the Hoffman product. Then from the Hoffman product add Br2, h20 and then A strong oxidizing agent like chromic acid to turn that secondary alcohol into the ketone. The final product would be your 1,-bromo-2,-butanone

Interesting, but you made me think... Wouldn't it be easier if you start with 1-butene, then Br₂ and H₂O to get the bromohydrin? And finally, oxidation...

[rwiew]

I don't know why you guys are not liking the bromination of an enolate. I would trap it into a silyl enol ether to be sure though - so 1) LDA 2) TMSCl (this will form a kinetic silyl enol ether), then Br2 should be ok (see e.g. http://pubs.acs.org/doi/abs/10.1021/jo00925a051) or NBS if need be?

[orgopete]

Edit

Re: bromination of enolate

What do you think might happen mid-reaction? Does your product know it shouldn't react? Why does basic bromination give bromoform? Would you get monobromomethyl ketone if only one equivalent of bromine were used? 

@quantum, could you make the bromoketone in two steps from acetylene?

[rwiew]

Who are you asking these questions orgopete? They don't apply to method, yet you're not quoting anyone else and writing under my post...

[AromaticAcrobatic]

Quantum,
Yup, your right it would be easier to start with 1-butene. I was just starting from a bare bones molecule to sort of methodically work our way up to the target molecule.

[quantumnumber]

I don't know why you guys are not liking the bromination of an enolate. I would trap it into a silyl enol ether to be sure though - so 1) LDA 2) TMSCl (this will form a kinetic silyl enol ether), then Br2 should be ok (see e.g. http://pubs.acs.org/doi/abs/10.1021/jo00925a051) or NBS if need be?

Many thanks! That was my first plan, I write it down.

[quantumnumber]

Edit

Re: bromination of enolate

What do you think might happen mid-reaction? Does your product know it shouldn't react? Why does basic bromination give bromoform? Would you get monobromomethyl ketone if only one equivalent of bromine were used? 

@quantum, could you make the bromoketone in two steps from acetylene?

I know basic bromination would get bromoform, but isolating the enolate equivalent (lithium enolate) and then mixing it with Br₂ I thought it could work, because it's supposed you don't have base anymore...

[orgopete]

Edit

Re: bromination of enolate

What do you think might happen mid-reaction? Does your product know it shouldn't react? Why does basic bromination give bromoform? Would you get monobromomethyl ketone if only one equivalent of bromine were used? 

@quantum, could you make the bromoketone in two steps from acetylene?

I know basic bromination would get bromoform, but isolating the enolate equivalent (lithium enolate) and then mixing it with Br₂ I thought it could work, because it's supposed you don't have base anymore...

I thought an enolate or enolate equivalent would react with the product as the reaction took place. A second reaction might be since the product is a stronger acid than starting material, I also expected proton exchange. I presume that is why haloform reaction is able to attack least substituted carbon over other reactions. If bromination of enolate worked as proposed, I would have expected it to be the preferred route.

@rview, you are correct. I had failed to read your post completely and discover you had linked it to a successful lit procedure. Mia culpea.

[Babcock_Hall]

What about starting with 1-butene, making the bromohydrin with NBS in aqueous DMSO, then oxidizing the alcohol to a ketone?  Offhand, I don't have an oxidant picked out.

[rwiew]

I thought an enolate or enolate equivalent would react with the product as the reaction took place. A second reaction might be since the product is a stronger acid than starting material, I also expected proton exchange. I presume that is why haloform reaction is able to attack least substituted carbon over other reactions. If bromination of enolate worked as proposed, I would have expected it to be the preferred route.

@rview, you are correct. I had failed to read your post completely and discover you had linked it to a successful lit procedure. Mia culpea.

I see - the attack on the product by the enolate is a reasonable worry, as is proton exchange - but I'd argue that the enolate should be so reactive that if you flood it with a few equivalents of the brominating agent, whatever it'd be, the bromination should be by far the fastest route available. Also, this is why I went for the silyl ether- it should decrease the reactive of the enolate for those potential side reactions and give you a clean attack on the desired electrophile.