[herrhansen]

Hi everybody.

I am planning the synthesis of the above aldehyde starting from 3-hydroxybenzaldehyde by first doing a Williamson ether synthesis and at last obtain the 2,3 dihydrobenzofuran by a Friedel craft ring closure.

I have attached the scheme.

I would really appreciate comments or suggestions, as I am in doubt if I can do the transformation on the unprotected aldehyde or if the synthesis scheme seems right?

Thanks everyone.

[discodermolide]

Hi everybody.

I am planning the synthesis of the above aldehyde starting from 3-hydroxybenzaldehyde by first doing a Williamson ether synthesis and at last obtain the 2,3 dihydrobenzofuran by a Friedel craft ring closure.

I have attached the scheme.

I would really appreciate comments or suggestions, as I am in doubt if I can do the transformation on the unprotected aldehyde or if the synthesis scheme seems right?

Thanks everyone.

Use K2CO3 and acetone at reflux for the alkylation of the phenol, the aldehyde should survive, but I guess you will need it protected anyway for the Friedel-Crafts

[herrhansen]

Thanks for your answer.

You are right it would be alot easier to carry it out the old great way.

Thanks.

[opsomath]

My favorite recipe for phenol alkylation is 1.1 equivalent of potassium hydroxide in DMF, powder the KOH in a mortar and pestle then add it to the phenol, then add the alkyl halide after 5-10 minutes. You can heat to 60-70 degrees if you find it necessary, although in your case I would be concerned about phenol-aldehyde condensation. Actually, I'd be concerned about it in general. Also, 1-bromo-3-chloropropane is readily available as a DNA extraction reagent and will alkylate more easily; that, adding catalytic KI, or both may be necessary.

[discodermolide]

My favorite recipe for phenol alkylation is 1.1 equivalent of potassium hydroxide in DMF, powder the KOH in a mortar and pestle then add it to the phenol, then add the alkyl halide after 5-10 minutes. You can heat to 60-70 degrees if you find it necessary, although in your case I would be concerned about phenol-aldehyde condensation. Actually, I'd be concerned about it in general. Also, 1-bromo-3-chloropropane is readily available as a DNA extraction reagent and will alkylate more easily; that, adding catalytic KI, or both may be necessary.

Grinding KOH makes it very hydroscopic. DMF is a difficult (please do not swear) solvent to remove. I have done such phenol alkylations on a scale of >250Kg, K2CO3 acetone reflux works every time.

[opsomath]

You're not kidding about the hygroscopic thing, buddy, I did my PhD in Georgia. You don't want to leave the powder lying around, but grind it fresh. I love DMF, I would always pour the reaction onto a beaker of fresh ice, set the resulting chemical Slurpee aside, and filter off brown-white flakes of >90% purity after the ice melted. Phenol ethers tend to recrystallize beautifully, too. Very easy and satisfying to make.

I can see how DMF can suck if you're doing process-scale chemistry like you describe. Little lab tricks like I was doing don't scale up too well, and DMF is a real bastard to take off on vacuum or anything. I would always drown it (extract 3x water) if I was unfortunate enough to be isolating a liquid organic product from DMF.

No doubt K2CO3/acetone would work just fine too. I'm just not experienced with it. I do wonder however if there might be some advantage to keeping this rxn at RT, since he has the mixture of aldehyde and phenolate?

[discodermolide]

You're not kidding about the hygroscopic thing, buddy, I did my PhD in Georgia. You don't want to leave the powder lying around, but grind it fresh. I love DMF, I would always pour the reaction onto a beaker of fresh ice, set the resulting chemical Slurpee aside, and filter off brown-white flakes of >90% purity after the ice melted. Phenol ethers tend to recrystallize beautifully, too. Very easy and satisfying to make.

I can see how DMF can suck if you're doing process-scale chemistry like you describe. Little lab tricks like I was doing don't scale up too well, and DMF is a real bastard to take off on vacuum or anything. I would always drown it (extract 3x water) if I was unfortunate enough to be isolating a liquid organic product from DMF.

No doubt K2CO3/acetone would work just fine too. I'm just not experienced with it. I do wonder however if there might be some advantage to keeping this rxn at RT, since he has the mixture of aldehyde and phenolate?

Could be there may be a problem with the phenolate and the aldehyde, but he has to protect it anyway for the Friedel-Crafts, so he may as well do it first. Apart from that KOH pellets are damm hard, I think the powdered form is commercially available?

[opsomath]

It sounds like the OP is not necessarily sure about the protecting group. What group is appropriate here? Dithianes and acetals should be labile to FC conditions.

[discodermolide]

It sounds like the OP is not necessarily sure about the protecting group. What group is appropriate here? Dithianes and acetals should be labile to FC conditions.

The acetal group should be stable to the FC conditions, but not the work up, where it should fall off, which is what you want anyway.

[herrhansen]

So great to see your discussions.

Helped alot. I really appreciate it. I think I will go for the acetal protection, but is it labile for the formed HCl from the two other reactions or do I need to add a base to quench the formed HCl?

Thanks

[discodermolide]

So great to see your discussions.

Helped alot. I really appreciate it. I think I will go for the acetal protection, but is it labile for the formed HCl from the two other reactions or do I need to add a base to quench the formed HCl?

Thanks

As the Freidel-Crafts is usually an aqueous work up you will need to add base to quench the HCl, or, with no added base the aldehyde may be able to be isolated directly

[orgopete]

When I did Friedel Crafts acylations, I worked them up with acid. Aluminum salts are messy.