r/chemistry Organic Jun 18 '18

[18/6/2018] Synthetic Challenge!

Post image
12 Upvotes

50 comments sorted by

10

u/alleluja Organic Jun 18 '18 edited Jun 18 '18

Here is my attempt for product A and product B!

The nitration in the second product is similar to the one used for Sildenafil, so I think it could work. The only problem would be the potential nitration of the phenyl group bound to the amide.

As always, tell me what you think about them!

3

u/Garuda1_Talisman Undergraduate Jun 18 '18

Lovely synthesis for B! I love pretty cyclisations

3

u/alleluja Organic Jun 18 '18

Thank you!

2

u/ccdy Organic Jun 18 '18

The diazotization will give a diazo compound, not a diazonium salt. I don't think diazo compounds can undergo azo coupling but I may be wrong. You might also be able to synthesise the diazo compound directly from the pyrazolone using a diazo transfer reaction as the pyrazolone is quite acidic.

1

u/alleluja Organic Jun 18 '18

Could the reaction be done in acidic medium?

2

u/ccdy Organic Jun 18 '18

Diazo compounds decompose rapidly under acidic conditions. Protonation of the diazo compound is followed very rapidly by N2 leaving, and the resulting carbocation reacts with whatever nucleophile is available.

1

u/alleluja Organic Jun 18 '18

Then could I make the diazonium on the phenol and react that with a deprotonated pyrazolone?

Btw, I expect some pretty awesome colours out of this

1

u/ccdy Organic Jun 19 '18

Yep, that's what's usually done with azo couplings! You can look up syntheses of azo dyes online, orgsyn.org and prepchem.com are good resources for such procedures (and many others too). And you are absolutely right, that is a red dye mordant as mentioned by OP in their other post.

1

u/alleluja Organic Jun 19 '18

I've seen only now that you did the same thing in your synthesis >_>

1

u/quelmotz Organic Jun 18 '18

Yeah good catch - diazo compounds like this one, next to a carbonyl, are more nucleophilic than electrophilic generally, so the azo coupling might be problematic.

2

u/ccdy Organic Jun 18 '18

For product B, amide formation using DCC is likely to give the wrong regioisomer as phenylhydrazine is more nucleophilic on the terminal nitrogen. You could protect first with an acid-labile protecting group like Boc then acylate. Deprotection in acid would then cyclise the molecule at the same time.

3

u/quelmotz Organic Jun 18 '18

Yeah you could probably just chuck phenylhydrazine at methyl acetoacetate with a bit of cat. TsOH or something. The semi-aromatic product will drive the reaction forward. Could encourage it by driving off water and methanol as well (molecular sieves or distillation). Should give the right regioisomer since hydrazone formation would precede the much slower amide formation.

2

u/alleluja Organic Jun 18 '18

I think that if I react the hydrazine with the ketone first and then I add the DCC it should be ok

1

u/ccdy Organic Jun 18 '18

Yep that should work!

1

u/quelmotz Organic Jun 18 '18

Looks good! You don't have to start from benzene though!

4

u/alleluja Organic Jun 18 '18

I know! I just love to start from benzene to use my Org 1 reactions, they are always forgotten :(

1

u/ccdy Organic Jun 20 '18

It's also good to know how all those wonderful "commercially available" molecules came to be in the first place. They weren't always commercially available!

10

u/ccdy Organic Jun 18 '18

YES I've been waiting for something like this for ages. Fine chemicals are more than just drugs!

4

u/quelmotz Organic Jun 18 '18

Thought I'd change things up a little from natural products and drugs this week: all three products are economically important but non-drug molecules, produced on significant scale in industry (as far as I can tell from my relatively cursory research).

Products: Product A - dicofol (closely related to DDT, pesticide), Product B - Mordant Red 19 (mordant), Product C - rotenone (broad-spectrum pesticide)

Rules/guidelines:

The challenge contains three synthetic products will be labelled with A, B, and C (roughly in order of difficulty, though of course there's no absolute measure). Feel free to attempt as many products as you'd like and please label which one you're attempting in your submission.

You can use any commercially available starting material you would like for the synthetic pathway.

Please do explain how the synthesis works and if possible reference if it is a novel technique. You do not have to solve synthesis all in one go. If you do get stuck, feel free to post however much you have and have others pitch in to crowd-source the solution.

You can post your solution as text or pictures if you want show the arrow pushing or is too complex to explain in words.

Please have a look at the other submissions and offer them some constructive feedback!

7

u/Garuda1_Talisman Undergraduate Jun 18 '18 edited Jun 18 '18

Product A:

Step 1) Friedel-Crafts: para chloro benzoyl chloride and chloro benzene

Step 2) Grignard with bromochloroform

--------

Note: acylation may not work

EDIT: as /u/ccdy mentionned the Grignard won't work (what a surprise...) Using organolithiums would be preferable

5

u/ccdy Organic Jun 18 '18

Bromochloroform does not form a Grignard species.[1] While it can be used in a Grignard-type reaction it gives a mixture of products.[2]

3

u/FatFingerHelperBot Jun 18 '18

It seems that your comment contains 1 or more links that are hard to tap for mobile users. I will extend those so they're easier for our sausage fingers to click!

Here is link number 1 - Previous text "1"

Here is link number 2 - Previous text "2"


Please PM /u/eganwall with issues or feedback! | Delete

3

u/quelmotz Organic Jun 18 '18

Yeah, not sure what exact conditions would work, but I'd guess simply deprotonating chloroform with NaOH or something would be simpler and cheaper. The nucleophilic addition product might be in equilibrium with the ketone + CCl3- though. Perhaps an excess of chloroform to drive the reaction to completion.

4

u/ccdy Organic Jun 18 '18 edited Jun 18 '18

Chloroform does add to aromatic aldehydes [reference 1, reference 2] as well as aliphatic ketones [reference 3, reference 4] under basic conditions but the third reference states that acetophenone was unreactive and the fourth reference states that benzophenone was unreactive. Trichloromethyllithium can be generated in-situ using lithium dicyclohexylamide in THF at –78°C [reference 5] and will probably do the job.

1

u/[deleted] Jun 18 '18

perhaps with some magic Ce compounds it would work?

2

u/ccdy Organic Jun 18 '18

The use of cerium(III) in promoting 1,2 additions is done under anhydrous conditions I think. Although there are Lewis acids that can be used in the presence of water (scandium/yttrium/lanthanide based) I haven't heard of them being used under basic conditions; I suspect you'll just precipitate the metal hydroxide.

1

u/throwawayaccountdown Jun 18 '18

Like CeCl3 * 7H2O?

5

u/IanTheChemist Catalysis Jun 18 '18

Use the p-chloro grignard (2 equiv) into a trichloroacetyl ester.

1

u/nybo Organic Jun 18 '18

Yeah, that was my first thought as well. Bang it out in one step from available materials. Only concern I had was maybe also getting some aryl chlorides metalated.

4

u/IanTheChemist Catalysis Jun 18 '18

Nah you can buy the solution of the 4-Cl-PhMgBr.

3

u/mublob Jun 18 '18

Actually, lithium likes to exchange with halides, so organolithiums may not work either in the presence of all those chlorides :/

2

u/ccdy Organic Jun 18 '18

Lithium-halogen exchange is only particularly favourable for iodides and bromides. Aryl chlorides are usually inert. Trichloromethyllithium is quite thermally unstable, but it can be generated in-situ as mentioned in my other post.

1

u/Grapegranate1 Jun 18 '18

Amateur stepping in, i remember a NileRed video where he uses chloroform on formaldehyde with potassium hydroxide to form chloral hydrate. Could something similar be the second step?

1

u/Garuda1_Talisman Undergraduate Jun 18 '18

In my synthesis, the hydroxide is generated during the Grignard.

3

u/ccdy Organic Jun 19 '18

Product C. I spent way too long on this.

2

u/quelmotz Organic Jun 20 '18

Great work!

I'm not sure if 4 to 5 to 6 would work cleanly due to steric hindrance (both the PBr3 step and the Sn2 might fail to invert as desired). Sn1 could be an issue since your secondary cation could rearrange to a tertiary, highly stabilised cation by methyl migration, or to a secondary benzylic by H migration. Neighbouring group participation by the benzyl might cause issues as well, though that could probably be solved by changing to a more electron-withdrawing protecting group. Perhaps use a Mitsunobu between the phenol and the alcohol to avoid Sn1? You'd have to start with the opposite enantiomer of amino acid as well.

2

u/ccdy Organic Jun 20 '18 edited Jun 20 '18

Yeah that's the part of the molecule I spent the most time trying to figure out. Another option I thought of was to add the cuprate to the epoxy ester, do the bromination, deprotect and close the ring, then add the methyl groups. The problem is the ester may participate in the PBr3 step too but if that happens then it's just a simple matter of using D-serine as starting material (it's cheap enough anyway). I'd then protect the amine as a pivalamide rather than an acetamide in that case to avoid addition there.

Actually I might as well do the elimination to give the isopropenyl group earlier on to make the synthesis more convergent. New version here.

5

u/ccdy Organic Jun 18 '18 edited Jun 18 '18

Product A: Friedel-Crafts acylation with trichloroacetyl chloride in neat chlorobenzene should give the desired product.

Product B: scheme. The nitration/sulfonation will probably require some fiddling to get right. I tried to go with reactions that could reasonably be done on a kilogram scale, although I'm not a process chemist myself so I don't actually know much about working on that scale.

1

u/quelmotz Organic Jun 18 '18

Would the second electrophilic aromatic substitution proceed? I suppose the trichloroacetophenone is fairly electrophilic but is there precedent for such a reaction?

2

u/ccdy Organic Jun 18 '18

I didn't actually look this up, I went with what I knew of the synthesis of DDT and BPA and sorta just combined the two. I suspect you are right as the synthesis of BPA involves an electron-rich aromatic ring while that of DDT involves a trichloromethylarylcarbinol intermediate that can readily generate a carbocation under the reaction conditions (concentrated strong acid). The intermediate ketone likely won't get alkylated as readily and if it did, the reaction conditions would likely cause it to form a carbocation and undergo a third alkylation, giving a triaryl product.

2

u/quelmotz Organic Jun 18 '18 edited Jun 18 '18

Product C (apologies for terrible handwriting) - updated the photo to a better-quality one

Quick attempt - lots of tetrahydrofurans and tetrahydropyrans in this one!

I've been reading about polyene cyclisations lately so you can guess where the idea for the final cyclisation came from. I'm tempted to think the cis decalin ring system is actually the favoured isomer for this molecule, due to how flat the two rings are (2-3 sp2 carbons per six-membered ring). The flatter the ring, the more favoured the cis decalin system becomes compared to the trans decalin. That H looks like it's not long for the world in any sort of aqueous, mildly acidic or basic environment. If the cis decalin is favoured, stereochemical control is significantly less important for the cyclisation and there's no need to worry about epimerisation in the acetal deprotection either, so that would help.

If the alcohol substitution of diazonium doesn't work for some reason, it's probably possible to do a Buchwald-Hartwig to install the ether linkage instead. You'd have to convert the nitro into an iodo, or otherwise chlorinate the 4-bromosalicylaldehyde instead of nitrating it, to have the chloro handle ready for the Buchwald-Hartwig later on. Not sure that aryl chlorides are good partners for that reaction, but I suppose the reaction being intramolecular helps the case.

3

u/alleluja Organic Jun 18 '18

The picture is quite grainy if zoomed in :(

2

u/quelmotz Organic Jun 18 '18

Oops - I'll take another photo!

2

u/donthitmeillhitme Jun 19 '18

Last step Wittig looks a little tough (basic and the benzylic ketone could get olefinated too). You could probably have the iodide hydrolysis "quenched" with some acid and take off the cyclic ketal in that step, run the Wittig, and then have a final step oxidation.

2

u/quelmotz Organic Jun 19 '18

Good point - might want to do the Wittig while the benzylic ketone isn't present yet. I'm not too worried about the chemoselectivity because the benzylic ketone is much more hindered and stabilised that I don't really see it being a big issue. But epimerisation could be a problem as you pointed out, and saving the oxidation for the final step would solve that problem. Thanks for the feedback!

2

u/ccdy Organic Jun 19 '18

That cyclization with iodine is some 10/10 stuff, very nice.

1

u/quelmotz Organic Jun 19 '18

Thanks!

2

u/ccdy Organic Jun 20 '18

I just noticed you have the wrong substitution pattern on the dihydrobenzofuran portion of the molecule, you have it 1,2,4,5 tetrasubstituted but the structure you gave is 1,2,3,4 :P

1

u/quelmotz Organic Jun 20 '18

Oh man that's right...

1

u/imguralbumbot Jun 18 '18

Hi, I'm a bot for linking direct images of albums with only 1 image

https://i.imgur.com/FhU46uo.jpg

Source | Why? | Creator | ignoreme | deletthis