Retrosynthesis 5 - Organic Chemistry

[@ronmasse]

Fantastic. Looking forward to more!

[@CasualChemistry]

Thanks 😀 I'll be trying out loads of ideas over the summer because my real-life teaching load will be lower. Going to have a play around with some other branches of chemistry too, but will definitely be keeping the organic videos going.

[@Belgium121]

Top notch, cheers mate!

[@CasualChemistry]

Thanks 🙂

[@benscrafield9575]

It might be more efficient to do a Friedel-Crafts with a lactone followed by redox manipulations, or a redox-relay Heck, either of which leads to an aldehyde which can then do a Pictet-Spengler. Not knocking your route though!

[@CasualChemistry]

Thanks for watching. There's definitely alternatives - I definitely went for an old-school vibe for this video

[@victordonchenko4837]

Instead of a carbonyl reduction, can't you do a Friedel-Crafts alkylation at the para position with a allylic alkene, allowing a more stable allylic carbocation additionally conjugated into the carbonyl, then hydrogenate the alkene away afterwards?

[@CasualChemistry]

I’m assuming you mean using something like ClCH2-CH=CH-COOH (or the ester). I guess that might work but I’d worry you’d form the regioisomer as well in significant amounts due to that cation being delocalised. That also might be problematic both because conjugating a cation with a carbonyl probably isn’t as favourable in the first place.

[@ProfessorWaltherKotz]

That dislike must be from the Physics department

[@CasualChemistry]

😂

[@danielyanes5510]

Quality video

[@CasualChemistry]

Many thanks for the feedback 🙂

[@martinowton7210]

There is a problem with your use of AlCl3 for the two F-C acylations. AlCl3 will demethylate the anisole. You are better off using polyphosphoric acid for the tetralone formation and starting from p-Br-anisole, forming the Grignard and reacting with ethyl chlorosuccinate under Mn catalysis to introduce the 4-carbon acyl sidechain . I have used this chemistry extensively.

[@CasualChemistry]

There's definitely alternative options here like you suggest. I was aiming for keeping the discussion at a reasonably basic level to emphasise the disconnection strategy. I think the F-C acylations here would be pretty safe if done a low temperature under anhydrous conditions (and using anhydrous AlCl3) with the AlCl3 not in much of an excess. If it were in a big excess, the SN2 demethylation would be a risk with time, though I'd be more worried if I were using AlBr3. The Al-Cl bond is pretty strong due to good size/energy orbital matching, so there shouldn't be much chloride nucleophile kicking about. Also the anisole lone pairs I wouldn't have thought to be Lewis basic enough, both because of delocalisation and sterics, to make demethylation so competitive with the speedy F-C acylation for this system.

[@martinowton7210]

@@CasualChemistry As anisole is pretty reactive to F-C you could use a milder Lewis acid than AlCl3 which would reduce the risk of demethylation. FeCl3 would be a possibility

[@ammarhaider5453]

Where I get its Forward synthesis?

[@CasualChemistry]

I was experimenting with a shorter video here so it’s not drawn out in full - though the reagents and steps for a possible route are given on the purple arrows.

[@ammarhaider5453]

@@CasualChemistry i am pitty confused in just last step. (Step of Succinic Anhydride).

[@CasualChemistry]

The bit that isn’t on the slide is that the anisole (PhOMe) has a pi electron donating group on the benzene ring. So, as a nucleophile, the benzene is activated to attack ortho/para, and para is better reactivity on steric grounds. You add both AlCl3 and succinic anhydride, but you only generate a reactive enough electrophile when the ring is opened up as in the mechanism. The acylium is required as a powerful electrophile as the aromaticity is being broken on the benzene. Once the benzene has attacked through its para position, it will quickly rearomatise by losing a proton, and so you are left with the ketone and a carboxylate at the end of the dangling chain (probably with an Al atom stuck on it). When the reaction is complete, you quench it out with an acid source like H3O+ which will both convert any remaining Al species into Al(OH)3 or Al(OH)4- which can be washed away into the aqueous layer of a separating funnel. This axis will also protonate the carboxylate to the carboxylic acid.

[@ammarhaider5453]

@@CasualChemistry This means alot. ❤️ Thank you so many much 💞

[@Sisi-ns8cd]

😍

[@CasualChemistry]

🙂 thanks for the feedback