[subu]

Help needed:
I have 1,3-diphenylbenzylamide (and 1,3-diphenylbenzylnitrile). I need to cyclize one of these to make an alpha-tetralone derivative.

I have tried to hydrolyze the nitrile to the acid but always got the amide derivative under both acidic (H2SO4, HCl, CH3COOH) and basic (KOH and NaOH) conditions. Hydrolyzing the amide also did not work out (H2SO4, TFA, MeSO3H, PPA, HCl). I tried to reduce the nitrile with DIBAL-H to aldehyde, but there was no reaction. The amide gave decomposed products with oleum. Friedel Crafts type cyclization of amide/nitrile with AlCl3, SnCl4 did not give desired products; got starting material back.

Can anyone suggest me ways to hydrolyze or carry out cyclization with this nitrile or amide. I would greatly appreciate any help provided.

Thanks in advance.
 

[orgopete]

Perhaps someone could draw this proposed reaction for me, but I can't figure it out. Anyway, I find this a bit of a surprise as amides are more basic than nitriles, so having an hydrolysis stop at the amide state is unusual. Since the nitrile does add water under acidic conditions, the amide must also protonate, therefore the rate of formation of the tetrahedral intermediate must be retarded in this example.

If a reaction is slow, then heat it and beat it. Phthalimides are acid stable, but they can also be hydrolyzed in acid if vigorous enough. (A work around in that case is to open with base to an acid amide and then acid hydrolysis of a normal amide.)

There was another question about the mechanism of base catalyzed amide hydrolysis. This is difficult because an amide anion (NH2^-) is not a weak base. Although this may increase the formation of a tetrahedral intermediate, it would not overcome the thermodynamic resistance of the hydrolysis. I can think of several work arounds. The nitrogen must be incorporated into a group that is less basic. Sulfonation could work, but that would leave an acidic NH. The nitrogen must be converted into something without an NH, like a pyrrole or N=NOH, etc.

Because I don't know the reactants, I can't rule out a Hoffmann rearrangement, diazotization to a bromide, and make the acid from it via a Grignard.

[subu]

Guess, it should have been 1,5-Diphenylbenzylamide (and 1,5-Diphenylbenzylcyanide) 
Two phenyl (Ph) groups at both the ortho positions of benzylamide (Ph-CH2-CO-NH2) or benzylcyanide (Ph-CH2-CN).

Sorry, I am unable to attach a chemdraw file; I am not getting the attachments option in additional options.

On one hand, sterics at both the ortho positions might seem to resist different reactions with the nitrile or the amide. But on the other hand, one can envision easy Friedel Crafts type reaction with either nitrile or amide to give the corresponding tetralone derivative.

I agree that the base hydrolysis of the amide would be difficult. But probably longer heating time would show some conversion (at least 50%?). But in this case, this did not help.

[subu]

Got it! Attached reaction.

[discodermolide]

Got it! Attached reaction.

Try making a model of the acid. I do not think it will cyclise.
This is a bi-phenyl system where the rings are not in the same plane but at 90° to one another.

[subu]

From the X-Ray data, the nitrile C (of CN) is ~3.5⁰ from the C of the phenyl ring where I wish to cyclise.
In the liquid state, I think free rotation around C-C bond attaching the two phenyl rings might come closer for some time (probably enough at the reaction time scale) to cyclize. Isnt this possible?

[discodermolide]

From the X-Ray data, the nitrile C (of CN) is ~3.5⁰ from the C of the phenyl ring where I wish to cyclise.
In the liquid state, I think free rotation around C-C bond attaching the two phenyl rings might come closer for some time (probably enough at the reaction time scale) to cyclize. Isnt this possible?

Sure this can be possible if the rate of reaction is similar to or faster than that of rotation.
To achieve the Friedel-Cafts you will need the acid chloride.

[fledarmus]

Actually, if you do a SciFinder search for the substructure with only two phenyl rings, this seems to be a fairly common reaction. A few examples:

Synthesis of methyl substituted benzanthracenes and benzanthracene derivativesFull TextBy Levy, Louis A. and Kumar V. P., Sashi From Tetrahedron Letters, 24(12), 1221-4; 1983 uses HF to close the ring,

The synthesis of 1,2,3,7,8,9-hexahydrodibenzo[def,mno]chrysene and the use of hydriodic acid-red phosphorus in the deoxygenation of ketonesFull TextBy Ansell, L. L. et al From Organic Preparations and Procedures International, 8(3), 133-40; 1976 uses ZnCl₂, and

An abbreviated synthesis of 7,12-dimethylbenz[a]anthracene and benzo[c]chrysene metabolites using the Suzuki reactionFull TextBy Sharma, Arun K. et al From Polycyclic Aromatic Compounds, 22(3-4), 277-288; 2002 uses MeSO₃H

[Dan]

Surely this ketone will exist as the phenol tautomer though?

[subu]

Most of the references refer to cyclization from acid, either by making acid chlorides or directly by using Lewis/ Bronsted acids. I also found couple of references that use nitrile or amide for cyclization. I was trying these methods since the hydrolysis to acid had not worked.
I imagine once the acid forms, it would be easier to cyclise compared to nitrile/amide.

yes, I haven't tried many other methods (thanks to the funding situation here)

As Dan expects, the ketone would exist as the phenol tautomer. This would be more challenging as I plan to do alpha acylation of the ketone and cyclise with the other phenyl ring
 

[orgopete]

Please describe your nitrile hydrolysis procedure that results in the isolation of the amide and your most vigorous attempts to hydrolysis it under acid catalysis.

[subu]

Nitrile hydrolysis : NaOH/EtOH/H2O, reflux for 48h. Continuing reflux for 4 days did not produce any acid nor affected yield of amide.
In H2SO4/CH3COOH, again only amide was formed but the yield was much low when compared to basic hydrolysis.

Amide hydrolysis: Further hydrolysis in KOH/DMSO (120C) was ineffective; isolated amide almost quantitatively.
Heating in 6N HCl, no change was observed; probably due to solubility.
In PPA (130 C), some dark brown material formed alongwith amide; H-NMR showed no peaks that could be from acid/ or tetralone derivative.
In conc. H2SO4 (rt and heated to 80 and further to 120 C), got some amount of amide back. Again no peaks in H-NMR that could suggest acid derivative.
In MeOH/conc.H2SO4, got back amide as such.

Nitrile with Cu(OTf)2 in CHCl3: no cyclization.
Nitrile with AlCl3 in Nitromethane: no cyclization.
Attempted direct cyclization of amide with SnCl4 in Acetonitrile, no reaction took place.
Nitrile in TFA/triflic acid (cat.) got amide derivative.
Amide in TFA/triflic acid (cat.) no transformation.

[orgopete]

I'm not necessarily convinced the lack of hydrolysis is due to any structural lack of reactivity. Most telling is the note that

Heating in 6N HCl, no change was observed; probably due to solubility.

I did a search for hydrolysis of phenylacetonitrile and found some conditions for arriving at the amide or carboxylic acid.

This is what I think. I think the insolubility is complicating your hydrolysis. In the case of basic hydrolysis, the insolubility results in a rate reduction. Additional solvent is diluting the base, reducing the concentration of dianion that must form and leads to an apparent failure to hydrolyze the amide. I saw a reference to an hydrolysis of the amide in 50% NaOH. You might try this as success of the reaction is probably visually evident by the amide dissolving if it forms the carboxylate.

I presume solubility is also limiting acidic hydrolyses. This is what I think might work. As I recall, one of my colleague hydrolyzed a phthalimide in 50% sulfuric acid by heating at reflux for ?? hours (days)? I think he used dioxane as a co-solvent. In this case, protonation of and attack upon a phthalimide is presumably the limiting step. This would be my preferred hydrolysis method. I think amides are more easily hydrolyzed under acidic conditions. But, solubility may reduce the effective concentration. With refluxing HCl, HCl can evaporate. Sulfuric will not and I think therefore the concentration can be made greater.

If you encounter the Bruckner-Wender eBook from a Google search, I don't agree with their suggesting that acid catalyzed amide hydrolyses are slower than nitriles. In my experience, nitrile hydrolyses can be stopped at the amide stage by using conc sulfuric acid and only using the number of moles of water present in it. Otherwise, I have found nitriles go all the way to acids. Both of us may be correct and the actual result will depend on the compound being hydrolyzed.