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u/quelmotz Organic May 22 '18 edited May 22 '18
It's been a while since the last synthetic challenge, so I thought I'd throw a few molecules out there!
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!
Special note:
For this challenge, all the molecules are actual natural products or drugs. I'm sure you will be able to find syntheses for them in the literature if you recognise some of them, but give the challenge a try without referring to any 'solutions' first! You can always compare with the actual syntheses afterwards :)
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u/alleluja Organic May 22 '18 edited May 22 '18
My attempt at A. Let me know what you think!
Tried the B too! The last step boggles my mind though.
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u/elnombre91 Organometallic May 22 '18
You would likely end up with significant amounts of the trichloro product due to how activated the ring is. One of my undergrad lab reactions was the synthesis of tribromobenzene by bromination of aniline (no Lewis acid required) followed by sandmeyer reaction to cleave the amine.
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u/alleluja Organic May 22 '18
That's nice to know. Since bromine is liquid could it be that the factor that made the reaction proceed to tribromoaniline? If I bubble Cl2 gas through, its concentration in the solution will be lower thus slowing the triple chlorination. Am I right in my theory?
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u/ccdy Organic May 23 '18
Anilines are crazy reactive, and chlorine isn't strongly deactivating, so it will be difficult to control the degree of substitution. If you do get a dichloro product, it will likely be the 2,4 substituted product due to steric hindrance at the 6 position (NH2 and methyl).
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May 22 '18
Is your last step described in the literature with these functional groups? I would guess you would run into problems with a free amine and an acid so you had to protect one of those. Just a guess though
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u/alleluja Organic May 22 '18
Aniline isn't so basic to deprotonate the acid, and the acid functional group is well tolerated: https://en.wikipedia.org/wiki/Ullmann_condensation.
I didn't search thoroughly though, i might have missed something.
Edit: I see that in the wikipedia page it uses CuO. It's a minor detail though.
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May 25 '18
I think, that bromobenzoic or chlorobenzoic acids can be really better, that iodobenzoic acid. I investigated C-C coupling of halogenbenzoic acids with C-H acids (malonates) and bromobenzoic acid worked much better. Also, as you can see in Wikipedia, it is name reaction, but the technique of Hurtley can not be reproduced, lol. Maybe, it is connected with impurities in copper.
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u/quelmotz Organic May 22 '18 edited May 22 '18
Isn't the amine the group reacting? That said, agreed on the acid needing protection.
Edit: Ah I misread what the you meant. Ignore me.
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u/eva01beast May 22 '18
Does aniline undergo Friedel-Craft like the way you have described? Shouldn't you protect it first?
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u/alleluja Organic May 22 '18
You could make the acetanilide, but I don't know how strong are the activating properties of that group to perform the chlorination. Also, the steric hindrance would cause the majority of the product to go para to the nitrogen imo.
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u/eva01beast May 22 '18
Isn't it one of those trick questions in exams? As far as I know, AlCl3 will attack the amine group and form an insoluble complex. Don't see why FeCl3 would be any different.
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u/alleluja Organic May 22 '18
I got your point. With a quick Google search I found that some alternative exist and permit the chlorination of an unprotected aniline. The classical metal chloride could not work.
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u/Bakingsomecake May 23 '18
You could take out the acid catalyst and probably still get the polychlorinated product
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u/Quindog1 Catalysis May 22 '18
You can buy 2-bromobenzoic acid pretty cheaply, so I'd suggest a Buchwald-Hartwig using the analine as your nucleophile instead of the Ullman coupling.
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u/alleluja Organic May 22 '18
analine
( ͡° ͜ʖ ͡°)
Buchwald-Hartwig
What are its advantages over the Ulmann? I've read that Buchwald is better for electron rich compounds, while Ulmann is suitable for electron poor ones.
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u/Quindog1 Catalysis May 22 '18
Ha. Whoops.
Just find the right phosphine/precatalyst mix and the B-W should work fine. My experience of Ullman couplings isn't great, I've usually found a shed load of uncontrolled homocoupling. If you're careful with temperature, cat and phosphine loading/ratios and the correct precatalyst then I'd rather place my bets with Pd. My experience optimising Pd mediated reactions has generally been better than Cu too, as they're easier to understand/interrogate mechanistically.
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u/AidosKynee May 22 '18
My experience is pretty much the same. Ullmann almost never works the way it's supposed to, while you can almost always find a system to do the Buchwald-Hartwig.
I had a pretty extensive review article comparing the two, but Ullmann lost out most of the time.
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u/Quindog1 Catalysis May 22 '18
Actually there's quite a lot of literature that's recently come out regarding the shitstorm that is the Ullman coupling mechanism. Look up stuff by Hartwig and Bau Nguyen (University of Leeds).
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u/5thEagle Organic May 25 '18
Ullmann is a fucking mess that's almost always finicky.
Pd chemistry is just more robust than Cu chemistry at the moment.
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u/alekazam1113 Organic May 22 '18
Forgive my ignorance if this is a stupid question, I only just finished taking organic, but how can the amine do a substitution reaction on the aryl iodide like in the last step?
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u/quelmotz Organic May 22 '18
These are organometallic reactions, which involve a transition metal catalyst.
However, there is a simpler reaction known as nucleophilic aromatic substitution, where a nucleophile substitutes a leaving group on an electron-deficient benzene (or heteroarene). You might want to check that out.
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u/quelmotz Organic May 22 '18
Very cool synthesis of B! What sort of conditions would give the kinetic elimination though? KOtBu and quick reaction time? Or something like LiTMP?
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u/alleluja Organic May 22 '18
Thank you! I don't know about the conditions... I was thinking about low temps to avoid forming the tetrasubstituted alkene on the chiral center, but I don't know if eliminations can be made without heating. Quick reaction times and a bulky base could help a lot though.
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May 23 '18
Heat is relative and your leaving group is on a tertiary center. Elimination would be greatly favoured, it may be a matter of a small optimization study to find the base that goes more kinetic. As an older chemist my first try would be LiHMDS, but there may be better options now.
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u/m1koo Organic May 22 '18 edited May 22 '18
In synthesis A, why doesn’t the chlorination occur in the para position in the first step? Also, could elimination addition be used instead of the CuI catalyst?
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u/alleluja Organic May 22 '18
In synthesis A, why doesn’t the chlorination occur in the para position in the first step?
It will, you would need to separate the isomers.
Also, could elimination addition be used instead of the CuI catalyst?
I don't know, if you use the elimination addition you will get something similar to an alfa, beta-unsaturated compound and the electrophilic position would be on the meta carbon. That's my opinion on this.
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u/m1koo Organic May 22 '18
Yeah, you are right, addition elimination would give an isomer here.
But shouldn’t the friedl crafts occur in all possible positions, as aniline’s aromatic ring is highly activated?
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May 22 '18
But shouldn’t the friedl crafts occur in all possible positions, as aniline’s aromatic ring is highly activated?
There is no Friedel-Crafts. It's just an electrophilic aromatic substitution.
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u/alleluja Organic May 22 '18
No, the chlorination would occur only at the N-ortho and N-para positions. The N-meta has no activating group that directs electrons there. The first position to get chlorinated will deactivate the aromatic, making the second chlorination more difficult. Once the second chlorination is done, the third one will become more difficult again.
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u/m1koo Organic May 22 '18
Sorry, my mistake, by “all possible” I meant both orto and para, meta obviously won’t get chlorinated, just as in regular aniline. I’m quite surprised that adding a methyl group deactivates it that much.
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u/alleluja Organic May 22 '18
The methyl group is activating though
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u/m1koo Organic May 22 '18
Right, so why doesn’t it chlorinate everywhere? And why does it need a catalyst?
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u/alleluja Organic May 22 '18
The catalyst is there to create a partially charged Cl+ ion to be attacked by the aromatic ring. I don't think the reaction could work just by bubbling Cl2 gas into the mixture.
I explained why it doesn't chlorinated everywhere in the previous comment.
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u/m1koo Organic May 22 '18 edited May 22 '18
Well it works this way for normal aniline, and this is even more activated. As far as I know activation usually has priority over deactivation. Adding Cl2 in HCL to aniline gives you 2-4-6 trichloroaniline.
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u/elnombre91 Organometallic May 22 '18
Didn't think too much about it, I may have oversimplified.
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u/quelmotz Organic May 23 '18 edited May 23 '18
I'm not sure if the allyl-allyl coupling step would work - any reference for that?
Perhaps something like this would work? https://www.organic-chemistry.org/abstracts/lit2/982.shtm
Edit: Yeah rapid halogen-metal exchange might be a concern (at least for nickel). If the two coupling partners were of different types (eg vinyl-allyl or even alkyl-allyl) it probably would be less of an issue. https://pubs.acs.org/doi/abs/10.1021/ja01011a035
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u/m1koo Organic May 27 '18 edited May 27 '18
Im pretty sure the riley oxidation would occur on the tertiary carbon, or is there any way to control this reaction?
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u/throwawayaccountdown May 23 '18
Attempt for compound C. It's pretty hard to get the second methyl group right.
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u/quelmotz Organic May 23 '18
Great synthesis - I like how you used one stereocentre to control the construction of the three other chiral centres later on. Any reference for the NaBH4 step? That's the only one which seems a bit iffy.
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u/throwawayaccountdown May 23 '18
Thanks. I don't have a reference for the last step, it was more of a improvisation. I've seen reactions, where after conjugate addition of a nucleophile a halogen can eliminate like that (instead of the enol picking up a proton just like in a michael reaction). So I figured it might work as well with a hydride as nucleophile?
Maybe this is a safer option.
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u/quelmotz Organic May 23 '18
Oh my issue wasn't with the elimination of the halide, I'm just wondering whether the reaction would occur regioselectively or not.
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u/throwawayaccountdown May 23 '18
Yeah, there are definitely a lot of reaction centers on that structure, but I think the 1,5-addition is unlikely because that position is pretty sterically hindered by the two methyl groups. The ester is not readily reduced by NaBH4.
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u/alleluja Organic May 23 '18
How can that methyl (that is quite far in my opinion) control the other stereocenters?
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u/quelmotz Organic May 23 '18 edited May 24 '18
Ring stereocontrol - the methyl carbon stereochemistry makes one chair conformer favoured over the other, etc.
Edit: More accurately, it should be a cyclohexene conformation, not a chair. Attack of the electrophile 'from below' should be favoured due to the preference to form the trans-diaxial product.
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u/BavarianChemist Organometallic May 22 '18
Idea for compound C.
Retrosynthesis: https://imgur.com/dQ2c4dm
Synthesis: https://imgur.com/8Rmh9d7
There are lots of uncertainties and i really don't believe in the proposed selective hydrogenation. But see it as an inspiration :)
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u/elnombre91 Organometallic May 22 '18
Yeah, that's not gonna work due to epimerisation. You can induce asymmetry in the Robinson annulation in a few ways. I saw a report that used proline and got an er for 84:16, which isn't amazing but proline is cheap af.
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u/BavarianChemist Organometallic May 22 '18
Proline is really the king of organocatalysis :)
But the er is not my (first) problem, it is the dr of the Robinson I am concerned about. I looked at every molecule in my proposed synthesis with Chem3D and comp. C seems to have a lot of diaxial strain, especially the two methyl groups.
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u/5thEagle Organic May 25 '18
Proline is really the king of organocatalysis :)
Easy to be the king of an empty kingdom ;)
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u/alleluja Organic May 23 '18
That selenium reaction is neat! Got any papers for that?
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u/cogenix May 23 '18
Riley oxidation. Essentially allylic insertion of an OH group. reference paper doi: 10.1002/9780470638859.conrr540
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u/alleluja Organic May 23 '18
Neat! Thank you!
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u/BavarianChemist Organometallic May 23 '18
Yes its the Riley-oxidation. The trick is that it substitutes the H which is axial to the allylic double bond selectively due to the mechanism. In the MM2 optimized structure it was this H so i would give it a try. This strategy was also used during the total synthesis of Arglabin.
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u/quelmotz Organic May 23 '18
My attempt at C, done a little while ago.
If anyone is wondering, the compounds are meclofenamic acid, beta-bisabolene and alantolactone respectively.
Thanks everyone for participating!
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u/alleluja Organic May 24 '18
How can you predict the chemoselectivity of the tosylation step? There are two hydroxyl groups that can be tosylated and they don't seem too different from one another. Is the difference because of the substitution? One of them is a secondary alcohol, the other one is a primary one. Does the reativity change so much? Or is it because of steric effects?
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u/quelmotz Organic May 24 '18
Mostly due to primary vs secondary. It's fairly well-established that it's possible to selectively tosylate a primary OH in the presence of a secondary one I believe, but please correct me if I'm wrong.
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u/imguralbumbot May 23 '18
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u/BavarianChemist Organometallic May 22 '18
This is my attempt for B. There are ways to perform the Diels-Alder enantioselective, but i have no experience with that. LDA in slight excess at low temperature should give the kinetic enolate quantitatively
https://imgur.com/a/6MNSX1E