[darkdevil]

Hi experts!
I was wondering why I failed in cyclizing the following compound (A). I tried to do the aldol condensation with with Potassium tert-butoxide in THF, but the final product is an amine (C), a hydrolyzed product of the starting amide (A) .



 I searched papers and reference about aldol cyclization and this reaction should be regarded as a "6-enolendo-exo-trig" reaction according to Baldwin's Rule. Some reference suggested to use aqueous bases like NaOH for the intra- cyclization, but my starting material contains an amide group. What conditions shall I provide in order to prevent the amde hydrolysis and at the same time cyclize (A) to give (B)?

Thank you very much!

[discodermolide]

Aldols don't usually go very well with amides.
For the hydrolysis to happen there must have been some water present perhaps?

[orgopete]

This looks messy. I think I would prepare a silyl enol imidate first. I think this can improve specificy of the enolization (which I think favors the ketone and its aldol). I think the nitrogen will improve the reactivity of the amide carbonyl group. Deprotection by fluoride can give the desired enolate.

[darkdevil]

Hi, THank you for your information.
I just wonder for these cyclization reactions, is it necessary to heat up the reaction? since it is an aldol condensation reaction. The eliminated product is water. I just wonder how can I improve the water elimination process??

[discodermolide]

Perhaps KO^tBu is not a strong enough base to deprotonate the amide. And this is the reason you ended up with hydrolysed amide. You assumed the reaction had worked, then worked it up under aqueous conditions and achieved amide hydrolysis by KOH?

[Dean]

The Aldol reaction requires a stable carbon anion. For this substance, I propose combination a diethyl malonate  with the ketone first, followed by decaboxylation & ring-closing.

[darkdevil]

Thank you for the suggestions..

What if I start with a compound like this (A') ? Where the ketone alpha proton is is absent ?? I still got the hydrolysis products ( an amine and a carboxylic acid)

[orgopete]

It is difficult to explain why this reaction is giving the products found, however one cannot overlook some factors. Even though a Claisen condensation of an ester can be catalyzed by an alkoxide, the reaction must overcome a big kinetic hurdle as alkoxides are much less basic than the ester alpha hydrogens. Consequently, the alkoxide and ester should match to mask ester exchange.

In this reaction, using an alkoxide with a vinylog of an imide increases the carbonyl reactivity compared with a simple amide. Since the isolated products are the cleavage products, the reaction is occurring at the carbonyl group. Furthermore, since two carbonyl groups are present, I am uncertain whether reaction is occurring at the desired center.

Changing the R-group could increase the alpha hydrogen acidity. Certainly other strategies could also be successful by an initial reaction on the "ketonic" carbonyl group and a secondary amide bond formation.

[discodermolide]

I would still suggest the following.
"Perhaps KOtBu is not a strong enough base to deprotonate the amide. And this is the reason you ended up with hydrolysed amide. You assumed the reaction had worked, then worked it up under aqueous conditions and achieved amide hydrolysis by KOH?"

[Dean]

What's the kind of carboxylic acid? That's the key to explain what happened.
1. According to your description, I don't think Aldol reaction has taken place. Only hydrolysis was performed. If you followed the reaction carefully, you would find which stage the hydrolysis happened. Are you sure that you used anhydrous THF? Did you dry the flask strictly? Was the reaction protected with nitrogen or argon?

2. With concerns of the formed water, try to add some molecular sieves to the reaction.

3. Try stronger bases under anhydrous conditions. 

[darkdevil]

Thank you..
The acid used is hexanoyl chloride. I did not use anhydrous THF, but the reaction was protected under N2 atmosphere.perhaps I will try again with everything in anhydrous conditions, and try to add molecular sieves.
Do I need really need anhydrous conditions since the aldol condensation would produce water at the end?

[Dean]

In my opinion, according to the current results, the first step is  avoiding the cause of hydrolysis, then try Aldol.

[darkdevil]

Thank you. I will keep it updated in this thread