Synthesis Question

[uselessprogress]

Okay i need a little help. I have to synthesize http://i39.tinypic.com/send5l.jpg Using a grignard reaction. I have two ideas right now. Let me know what you think.

 

http://i42.tinypic.com/r9jxix.jpg

 

and

 

http://i43.tinypic.com/2z7hegz.jpg

 

Thanks

[chemist]

Hello,

 

Please see this link to a chemdraw scheme I've made below:

 

http://picasaweb.google.com/lh/photo/-SbDv9deQWE1E9kI1zT__w?authkey=Gv1sRgCJuh7bCx65-CUQ&feat=directlink

 

sorry I didn't have time to figure out how to load this on the forum any other way..

 

let me know if you have any questions...

 

hope this helps.. : )

 

EDIT:

Sorry I threw that together quick.. I'm still at the lab..

but I should add that if your prof asks about a mixture of monoprotected and diprotected being formed you can tell him that the protection step can be done highly diluted to avoid that...

or you can also use 3-hydroxycyclohexanone... protect the alcohol...

do the gringnard... dehydrate the alcohol formed in the gringnard and then deprotect the other alcohol and oxidize back to the ketone with PCC...

 

hope that helps..

Edited May 14, 2009 by chemist

[UC]

You won't be able to efficiently monoprotect one of the two ketones. Protection is done in an excess of alcohol with acid catalyst to ensure it goes to completion.

 

An ether protected 3-hydroxycyclohexanone is your best option, although using PCC to oxidize an alcohol is a waste unless acidified dichromate or another cheapo oxidizer won't work. PCC has the lovely distinction of having both pyridine, hexavalent chromium, and is typically used in dichloromethane. Acidified dichromate may have the hexavalent chromium, but has no need for pyridine or toxic organic solvent.

Edited May 14, 2009 by UC

[uselessprogress]

Thanks for the quick reply. My biggest question regarding the method you have addressed is whether the tautomerization of the cyclohexanone to its enol form will provide a stable enough compound to react via allylic free radical halogenation. Also, how do you feel about the other method? Every step seems correct with the possible exception of the hydroboration of the conjugated diene. I can find nothing indicating if this will work in the manner shown. The professor has acknowledged that there may be several correct syntheses. Any help you can provide will be greatly appreciated.

[UC]

You will not get allylic bromination on cyclohexanone. Ketones are rapidly halogenated in the alpha-positions by an electrophilic reaction involving the enol. Allylic brominations are usually done with N-bromosuccinimide in nonpolar solvent, where you will generate precisely none of the enol. Who's to say what side of the enol the bromine would attack anyway. You would get a mix of 2 and 3-bromocyclohexanones if it worked.

 

Also, you have the hydrolysis of a secondary alkyl halide with NaOH. If you've covered the E1,E2, SN1, and SN2 mechanisms, you know that secondary alkyl halides are fair game for just about any reaction mechanism, so you will probably get some elimination as well.

 

I'm pretty sure that you will get borane addition across both bonds, not just the one, adding an extra dehydration step.

 

You can come into chat if you'd like to discuss in person. Hit the "chat" button on the top menu bar.

 

Are you required to start with cyclohexanol?

Edited May 14, 2009 by UC

[chemist]

You won't be able to efficiently monoprotect one of the two ketones. Protection is done in an excess of alcohol with acid catalyst to ensure it goes to completion.

 

An ether protected 3-hydroxycyclohexanone is your best option, although using PCC to oxidize an alcohol is a waste unless acidified dichromate or another cheapo oxidizer won't work. PCC has the lovely distinction of having both pyridine, hexavalent chromium, and is typically used in dichloromethane. Acidified dichromate may have the hexavalent chromium, but has no need for pyridine or toxic organic solvent.

 

 

Hello,

 

The monoprotection works.. I do these all the time..

here are some references I quickly found on scifinder... I have my own procedure that utilizes a dilution method but these are published and provide decent yields as well...

 

Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (11), 2117-22; 1989 72% yield

 

 

Journal of the Chemical Society, Chemical Communications, (4), 364-5; 1993 52%

CASREACT

 

 

 

Justus Liebigs Annalen der Chemie, 665, 55-67; 1963 60%

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Merged post follows:

Consecutive posts merged

Hello,

 

The monoprotection works.. I do these all the time..

here are some references I quickly found on scifinder... I have my own procedure that utilizes a dilution method but these are published and provide decent yields as well...

 

Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (11), 2117-22; 1989 72% yield

 

 

Journal of the Chemical Society, Chemical Communications, (4), 364-5; 1993 52%

CASREACT

 

 

 

Justus Liebigs Annalen der Chemie, 665, 55-67; 1963 60%

 

EDIT: Sorry still posting from the lab...

you may also want to be careful about using the THP protection group if you're going to be following the synthetic route utilizing the 3-hydroxycyclohexanone because:

 

1. The THP will have a stereocenter once added

2. and even if the 3-hydroxycyclohexanone is not racemic - which would make it waay more expensive than PCC - you'll end up with a very nasty mixture of distereomers that will be a pain to separate and characterize...

 

just a thought...

 

Using PCC is more of a personal choice I guess.. I prefer to use it because it typically requires less equivalents.... plus my stuff tends to be really complicated so staying away from the harsher oxidizing/cheapo reagents is usually a good idea - but I'm not sure if in a theoretical situation the profs will care either way...

 

hope this helps. : )

Edited May 14, 2009 by chemist
Consecutive posts merged.

[UC]

Well, you can't argue with published procedure. I do not have access to those resources, but I'll take your word for it. Since I am in college and am heading for a career in organic synthesis, would you mind running through a general procedure for monoprotection, in PMs if you'd prefer. Do you use 1eq of the alcohol in an inert solvent with acid catalysis?

 

I rather like to have a realistic procedure, even if it is just a theoretical exercise. It's good practice.

 

Instead of THP, how about trapping one of the ketone functionalities as an enol ether with TSMCl? Or will that be unstable to grignard reagents? a dash of fluoride in the acidic workup and any diastereomer related problems go away.

Edited May 14, 2009 by UC

[chemist]

Well, you can't argue with published procedure. I do not have access to those resources, but I'll take your word for it. Since I am in college and am heading for a career in organic synthesis, would you mind running through a general procedure for monoprotection, in PMs if you'd prefer. Do you use 1eq of the alcohol in an inert solvent with acid catalysis?

 

Who said there was intent to isolate and characterize the intermediates? Post-grignard acidic workup should pop the THP off and return you to a single stereocenter, no?

 

Hello,

 

Oh sorry that you don't have access to those.. if you want to check them out you can go to your university library and they should have scifinder there.. if not they should have some other way to access online journals...

Then you just have to put in the info provided in the reference...

 

To your question...

THP is an okay protecting group.. but TBS or some other silyl protecting group would be better here because... THP can often get displaced by gringnards so that is another problem...

 

Yes you will be removing it but until you do the disastereomers will be a problem... Unfortunately you will have to characterize and isolate each intermediate - god I wish this wasn't so.. but alas it is.. : (

 

if you do not do so it will not be possible to do the next reaction without major problems...

 

I'd be happy to run through a procedure for the monoprotection for you... either by PMs or in another thread if you want - I'm not sure if I can do that here.. but if I can I'll post it here tomorrow if you want.. whatever is easier...

 

 

hope this helps : )

 

congrats on deciding to become a synthetic organic chemist.. I'm in a PhD program for chemistry right now - so I might be bias - but I think it's a great career choice. : )

[UC]

I edited some of my text while you were typing that. Sorry

 

I'm at home for the summer and scifinder is dead as a doornail off-campus as well.

[chemist]

Well, you can't argue with published procedure. I do not have access to those resources, but I'll take your word for it. Since I am in college and am heading for a career in organic synthesis, would you mind running through a general procedure for monoprotection, in PMs if you'd prefer. Do you use 1eq of the alcohol in an inert solvent with acid catalysis?

 

I rather like to have a realistic procedure, even if it is just a theoretical exercise. It's good practice.

 

Instead of THP, how about trapping one of the ketone functionalities as an enol ether with TSMCl? Or will that be unstable to grignard reagents? a dash of fluoride in the acidic workup and any diastereomer related problems go away.

 

Hello,

 

Unfortunately the silyl enol ether is also unstable with gringnards - but you're on the right track. : )

 

Also adding fluoride in the acidic workup will not really help you here..

It will actually complicate things a lot...

 

The problem is that as soon as you THP protect the alcohol you will have a mixture of diastereomers that you will have to purify via column chromatography before you can do the gringnard.. you cannot have any of the reactants or left overs from the quench / workup steps in your mixture when you attempt the gringnard..

 

Furthermore.. although it is tempting to find ways to combine reactions when you fist start out in synthesis it is never a good idea to do this because pushing on with crude and / or trying to add multiple steps in the same pot usually results in black gue...

 

When I monoprotect a symmetrical diketone I have the symmetrical ketone with catalytic amounts of acid in a round bottom with molecular sieves.. then using an addition funnel I add a dilute solution of the protection group drop wise in the appropriate solvent - the ratios for this solution depend on the protecting group/solvent etc...

 

Also.. the PCC is a realistic method.. often times harsh and/or acidic oxidizing agents can remove protection groups that are acid labile.. PCC is about 10cents more expensive per use than some of the other oxidizing agents because if your alcohol is secondary and stable it typically takes a lot more equivalents of these kinds of reagents therefore while the bottle is cheaper from aldrich in practice they are not cheaper per use... especially when they wreck your compound... : (

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Merged post follows:

Consecutive posts merged

I edited some of my text while you were typing that. Sorry

 

I'm at home for the summer and scifinder is dead as a doornail off-campus as well.

 

That sucks not having scifinder... I would go crazy without it and beilstein... those are like bibles to synthetic chemists...