Sciencemadness Discussion Board - How to selectively alkylate an aromatic ring?

How to selectively alkylate an aromatic ring?

Maui3 - 19-1-2025 at 13:46

I am looking to alkylate a benzene-deriative selectively multiple times. Are there any good ways to do this? I know a FC-alkylation will result in byproducts. I thought about maybe brominating, then doing a Wurtz-Fittig reaction, but I am not sure about how selective the bromination will be.

Note: I am running on very low sleep. I probably said some very confusing stuff in this post. I apologize.

DraconicAcid - 19-1-2025 at 18:48

It depends on what alkyl groups you want to put on, and where (and what else is on the ring). FC may result in rearrangement of the alkyl groups and multiple alkylations- one can get around that by acyalting the ring, and then reducing the acyl group to an alkyl one (at least, on paper).

Maui3 - 20-1-2025 at 00:38

I am planning on adding 2 isoamyl and 2 ethyl groups to catechol diacetate. I already have the bromides of them, so I would like if there was a way I could use them for this. Thanks for the response too :-)

Keras - 20-1-2025 at 01:11

I would try to add the ethyl groups first. You can use acetic anhydride for FC-acylation, then use Wolff-Kieshner reduction to turn your carbonyl group into alkane*. You do that twice, then you use FC-alkylation to attach your isoamyl groups at the remaining positions.

* You can’t acylate more than one position at a time because of the de-activating effect of the carbonyl group.

Esters, as far as I know, are weakly activating, so it should work.

Niklas - 20-1-2025 at 02:13

Attempting any type of FC reaction on catechol diacetate would likely cause a Fries rearrangement to occur as the primary reaction. You can use that to install the acetyl groups tho, and just wait with remaking the diacetate until having reduced and alkylated things.

Wurtz-Fittig wouldn’t really be an option on a catechol I believe, the diacetate would most definitely quickly be reduced via a Bouvault-Blanc resulting in the phenolate, which would then form an ether via a Williamson as a side reaction.

Maui3 - 20-1-2025 at 03:29

Thanks! This helps a lot. Considering both of your concerns and suggestions, would something like this be possible?

Keras - 20-1-2025 at 05:55

That’s the spirit, however I don’t see why you esterify the -OH groups if you plan to get the phenol at the end.

Also, I don’t know if acylation would happen in the ortho positions or para. Because para, ortho and meta mix up, I don’t think there’s any privileged position. Steric hindrance would probably lead the acyl groups to attach elsewhere (in 4 or 5, para to the hydroxy groups).

Maui3 - 20-1-2025 at 06:10

Thanks for the encouragement!

The reason for esterifying the -OH groups is that I am worried, that the acetic anhydride and isoamyl bromide will attach to the -OH groups (instead of on the ring) if the -OH groups are left un-protected.

Do you have any suggestions to increase the acylation on the desired positions? If acyl groups attach to the para position (and there isn't anything I can do about it), I would need to get some obscure reagent, that after the Wolff-Kieschner reduction would give the isoamyl group, right? Otherwise, I could possibly first attach the isoamyl with FC-alkylation, then the FC-acylation, assuming that the isoamyl group (in alkylation) will also attach to para position relative to the hydroxy groups.

DraconicAcid - 20-1-2025 at 07:16

The isoamyl groups will certainly rearrange if you try doing FC with isoamyl bromide.

Maui3 - 20-1-2025 at 07:37

How (or could) I prevent that? What about doing an acylation of the catechol with isovaleryl chloride, followed by the Wolff-Kieschner reduction - to get the isoamyl groups? I do really want to prevent using isovaleryl chloride. I haven't checked the price, but I am already sure it's very expensive, lol

DraconicAcid - 20-1-2025 at 07:40

The only alternative I can see is to halogenate the ring, and convert the isoamyl bromide to a Gilman reagent. But I only have experience with that reaction on paper.

Maui3 - 20-1-2025 at 07:49

Yes, that does not sound particularly fun, lol. Why wouldn't it work with isovaleryl chloride/bromide followed by the Wolff-Kieschner?

DraconicAcid - 20-1-2025 at 08:05

It would, but you said you wanted to avoid that.

Maui3 - 20-1-2025 at 08:15

Sorry, I see that I should have phrased it better now. I meant that I'd probably rather go through the hassle of making isovaleryl chloride than Gilman reagents.
If I decide to do the isovaleryl chloride-method, I should attach the isovaleryl chloride first, right? .. since it'll attach in the para positions relative to the OH groups.

[Edited on 20-1-2025 by Maui3]

Niklas - 20-1-2025 at 09:43

Quote: Originally posted by Maui3

Thanks! This helps a lot. Considering both of your concerns and suggestions, would something like this be possible?

There are two problems that come to my mind, most notably the fact that you most definitely won’t have ortho selectivity for the acetylation but rather para. So it‘d be best to go around this by installing the isovaleryl groups first using isovaleryl chloride, in which case you wouldn’t have to protect the phenol anymore, as you can purposely acylate the oxygen and then rearrange using AlCl3 (Fries rearrangement as stated before).
Other than that it’s just what’s already been said, you won‘t be able to do double acetylation, so you‘ll painfully have to install and reduce every ketone separately, and I can’t really think of a better method when starting from catechol.

DraconicAcid - 20-1-2025 at 10:22

Once word of note- I have smelled isovaleric acid, and would not want to work with the halide.

Our students roll dice to find out what acid they are going use for esterification in a particular lab- if they roll for isovaleric acid, they are permitted to roll again. If they dare use it, they are provided with a disposable lab coat for that experiment (which will be burned immediately afterwards), and are advised to bring a ziploc bag and a change of clothes. It's like a sockful of parmesan cheese that's been worn during a marathon and left behind the radiator for a month.

Maui3 - 20-1-2025 at 10:35

Niklas, that sounds very much fine to me. As long as it works (in theory), I won't complain, lol.

DraconicAcid, Haha, thank you for the story. It really does sound horrible. I do have these "coverall"s - if it smells that horribly, I could probably use them. I am quite sensitive to smells like "A sockful of parmesan cheese that's been worn during a marathon and left behind the radiator for a month.", so it's going to be really fun. I will update you all soon, as I'll probably do the experiment (isovaleric acid) tommorow - though not with the halide, as I do not have thionyl chloride on hand.

Last question (for now): I could probably research this myself, and I do feel I should research better first before asking, but I still feel you all might have some advice: are there other chlorinating agents that can be used to chlorinate carboxylic acids, that aren't thionyl/oxalyl/phosphorous chloride(s)? I don't imagine I could use TCCA or hypochlorites, but I am a bit unsure.

Niklas - 20-1-2025 at 11:19

Quote: Originally posted by Maui3

Last question (for now): I could probably research this myself, and I do feel I should research better first before asking, but I still feel you all might have some advice: are there other chlorinating agents that can be used to chlorinate carboxylic acids, that aren't thionyl/oxalyl/phosphorous chloride(s)? I don't imagine I could use TCCA or hypochlorites, but I am a bit unsure.

I think using TCCA actually is an option, even if works somewhat badly probably, but if I remember correctly it forms a type of Vilsmeier reagent with DMF (only required catalytically) which can be used to chlorinate carboxylic acids (and even be used in the formylation of aromatic compounds).

Alternatively I guess there is the otc approach via sulfur chlorides, could safe a little bit of effort at least by going via James Cambell‘s approach of directly mixing TCCA and sulfur, but either way that method is rancid tho..

Maui3 - 20-1-2025 at 11:21

Interesting Niklas! Thanks, I'll definitely look that up.

Maui3 - 21-1-2025 at 07:34

I am done with the isovaleric acid now. I should have bought scented candles before beginning the synthesis, lol. It smells quite bad.. and it lingers around. When I added the isoamyl alcohol to the nitric acid, and the NO2 was released, even just the small amount of particles of the isovaleric acid clinged to my fingers. I am writing this with a glove on my one hand, because it smells that horrible.

Anyway, I am quite happy with how it went.. though somehow it must've decomposed, since it had a camphorous-like smell once I was done. I was also a bit sceptical about the amounts of 80% nitric acid per isoamyl alcohol (85 g : 18 g) used, and since it started to fume HNO3/NO2-vapors when I was concentrating the solution, something was probably off with the nitric acid.

I am not sure if the nitric acid could decompose it? .. Anyway, it was as nightmare to make that big an amount of nitric acid, so next time it's KMnO4 for the oxidation.

DraconicAcid - 21-1-2025 at 10:11

Quote: Originally posted by Maui3

I am done with the isovaleric acid now. I should have bought scented candles before beginning the synthesis, lol. It smells quite bad.. and it lingers around. When I added the isoamyl alcohol to the nitric acid, and the NO2 was released, even just the small amount of particles of the isovaleric acid clinged to my fingers. I am writing this with a glove on my one hand, because it smells that horrible.

I waaaaarnnnned you!!!!!

Texium - 21-1-2025 at 10:56

Permanganate or dichromate is the way to go for sure. Nitric acid oxidations of alcohols are unreliable and may produce nitrate esters and other nasties.

Maui3 - 21-1-2025 at 12:19

DraconicAcid, You're right!! And thank you for that! At least that made my buy the "coverall"s, and I really appreciate I wore one of those now.
Texium, Thank you. I'll buy some permanganate or make some dichromate from forks now lol. If I use potassium dichromate for this oxidation, it has to be in a dilute sulfuric acid solution, right?

Maui3 - 23-1-2025 at 01:55

Since this is quite a long process (where a lot could go wrong), I just want to be sure I am doing the correct thing - even though I might be triple-checking.
Is this the idea (for now)?

I assume aaa lotttt of loss of product in all of these steps, so I think in some of the steps I won't isolate the compound, and just do the next reaction (if there are no biproducts).

Also, I had a hard time finding a procedure for the oxidation of isoamyl alcohol to isovaleric acid with potassium permanganate (though I did find one with dichromate). I finally found someone oxidizing the isoamyl alcohol with permanganate on youtube, but they only got a 5% yield (if I remember correctly). I would like to get more than a 5% yield, since the reagents are expensive lol. Is that low of a yield expected?

[Edited on 23-1-2025 by Maui3]

Niklas - 28-1-2025 at 04:43

Quote: Originally posted by Maui3

Also, I had a hard time finding a procedure for the oxidation of isoamyl alcohol to isovaleric acid with potassium permanganate (though I did find one with dichromate). I finally found someone oxidizing the isoamyl alcohol with permanganate on youtube, but they only got a 5% yield (if I remember correctly). I would like to get more than a 5% yield, since the reagents are expensive lol. Is that low of a yield expected?

Generally I would expect quite a bit higher for such a substrate, NileRed got 60% when oxidizing butanol for example (https://youtu.be/M8VSKqPYdHI?si=W5D8y9_pLo07mNnI), and this one shouldn’t be too different.
What I would do is to mix 1 eq of the alcohol with an aqueous solution of 0,4 eq sodium carbonate, add a solution of 2,2 eq potassium permanganate, let that stir for maybe two hours, acidify with sodium bisulfate, slowly add H2O2 until all the MnO2 dissolves, extract with ether, evaporate things down, and optionally distill under vacuum.

Regarding the plan, I see two issues with it:
First the minor one, as you have carbonyls on the substance you are acylating, you‘ll have to add at least as many equivalents of the lewis acid, as the carbonyls will all complex and therefore make it unreactive towards the desired ester carbonyls.
And now to the major one, the fact that you‘d be doing a Fries doesn’t change the issue of the already acylated ring just not being able to react further, so for each alkyl group you‘ll have to do a separate O-alkylation, Fries, Wolff-Kishner cycle, so it’s really going to be quite lengthy and annoying unfortunately..
Also I think you skipped a step on installing the acetyls? At least I don‘t think that type of acid catalyzed direct acetylation is an option here, as the phenol groups will most definitely react first, and I don’t know if catalytic p-TSA can properly mediate a type of Fries as well.

Something I didn’t consider before, you may have to do things in the order of installing one isovaleroyl group, then the two acetyls, and then the remaining isovaleroyl, as ortho should be favored as soon as that one bulky alkyl group is placed in para. Unfortunately that also comes with the downside that you can’t take a shortcut with the two ethyls being installed in one FC-alkylation (as you wouldn’t have to worry about over alkylation if it’s the last two), but would really have to do three steps for every alkyl chain..

Maui3 - 28-1-2025 at 08:26

Gotcha.

Yes, you are definitely correct - I forgot a step in installing the acetyls in the picture.

For the major issue, it's fine - I can do it like that.. What I am most worried about is how much product I am going to lose in the process. Do you think, for example following the alkylation to the fries, I do have to isolate the product? I expect if I just calculate how much AlCl3 to add, roughly, it will be fine. Though I'll have to remove side products first. Allso thank you very much for pointing it out! Looking on the bright side of things - I am going to walk out of this project as a expert in Alkylation, Fries, Wolff-Kinshner cycle, lol :p

So something like this?

NOTE: Like last time, I probably made a mistake in my chemdraw again. It's quite a lot to write haha.

Niklas - 28-1-2025 at 09:35

Yeah, that looks about right. I feel like a one-pot approach for the Fries and FC should definitely be possible, so that will save you some steps at least.

On a different note, I don’t know if that’s of any relevance to you, but I thought I’d share it anyway. I tried coming up with a less conventional approach where the ring is constructed from non-aromatic components (isohexanal and butanal), as for some highly substituted aryl structures that actually results in a shorter overall path. Just thought it was a nice little challenge, but maybe it can serve as inspiration for some future projects

bnull - 28-1-2025 at 09:35

Quote: Originally posted by Maui3

What I am most worried about is how much product I am going to lose in the process.

Three-fourths of the initial catechol at least.

Assume each step yields 90%, which would be wonderful. Being 12 steps, the final yield would be about 0.90¹² = 0.28 (28%) of the initial catechol. I don't think you would get very close to that actually.

Maui3 - 28-1-2025 at 09:44

Niklas, thank you! Sounds good - as always: I'll keep you guys updated - both with my succeses, and when I need help

!
Also, that approach is very interesting. I definitely serves as inspiration. Heck, I might even try it after this one. Since I don't have access to NMR, and my basic analysis methods are either melting point or biological (aka. tasting or smelling). It would be interesting to see if I got similar results. Haven't looked through your whole approach yet though - so I might not try it if it contains n-butyllithium or similar LOL.

Bnull, ah - thank you for your estimate. Assuming I do a one-pot I will probably save a lot of yield. But it would still suprise me if I got 28%.

clearly_not_atara - 29-1-2025 at 07:43

I don't think there is a one-pot solution to this. And that final acylation is not going to yield anywhere near 90%.

I like bnull's approach, at least on the side of the dienophile. However, I think I would replace his diene by 2,5-diethyl-3,4-diethoxyfuran, which in turn might be obtained by the dimerization of 1-chloro-1-ethoxy-2-butanone, the latter obtained by chlorination of 1-ethoxy-2-butanone, and that from the product of perethylation of glycolic acid and a selective addition of nucleophilic ethyl. This has the advantage of avoiding the smelly sulfur oxidation, and ensuring that the double bonds are in the appropriate orientation for the Diels-Alder reaction.

bnull - 29-1-2025 at 10:53

Quote: Originally posted by clearly_not_atara

I like bnull's approach, at least on the side of the dienophile.

It wasn't me.

Niklas - 29-1-2025 at 11:39

Quote: Originally posted by clearly_not_atara

However, I think I would replace his diene by 2,5-diethyl-3,4-diethoxyfuran, which in turn might be obtained by the dimerization of 1-chloro-1-ethoxy-2-butanone, the latter obtained by chlorination of 1-ethoxy-2-butanone, and that from the product of perethylation of glycolic acid and a selective addition of nucleophilic ethyl. This has the advantage of avoiding the smelly sulfur oxidation, and ensuring that the double bonds are in the appropriate orientation for the Diels-Alder reaction.

That‘s a good idea, actually thought of going via a furan derivative as well, tho I wasn’t sure how one could pull of a simple enough synthesis. What exactly do you imagine for the dimerization? I obviously see the Paal-Knorr part, but how would one do this Wurtz type reaction with the ketone still present?
I guess ketal protection could get around it, but combined with the fact that you would somehow have to obtain the 1-ethoxybutanone as well, that would result in quite a long path overall..
I agree on the sulfur aromatization being less than ideal tho, personally would want to avoid it as well xd. The obvious alternative would be some benzoquinone type oxidants, like chloranil or DDQ. Chloranil is available from paracetamol (https://youtu.be/Fr3__SWwpXc?si=lt2CLsX4QCVu1T5-), it is rather annoying in terms of solubility tho. Or one could attempt a Saegusa-Ito type oxidation as far as they have palladium on hand.

[Edited on 29-1-2025 by Niklas]

clearly_not_atara - 29-1-2025 at 17:31

The coupling is achieved directly by iron pentacarbonyl (the safest metal carbonyl):
https://pubs.acs.org/doi/pdf/10.1021/jo00981a011

as well as by reduced titanium isopropoxide:
https://www.thieme-connect.com/products/ejournals/abstract/1...

or by tetrakis(dimethylamino)ethylene:
https://www.sciencedirect.com/science/article/abs/pii/S00404...

or by the reduction product of NiBr2(PPh3)2 with Zn:
https://www.sciencedirect.com/science/article/abs/pii/S00404...

In our specific case, the compound is not only an alpha-chloroketone but an alpha-chloroether, both functional groups tending to increase the reactivity of the alkyl halide. My hunch is that a less active metal, like copper powder, might be sufficient to induce the reaction. The stability of the substrate may prove to be a greater challenge.

Niklas - 30-1-2025 at 14:08

Pretty neat, especially that approach using TIPT seems quite achievable. The use of NiBr2(PPh3)2 and Zn seems pretty good in terms of accessibility as well, tho they seem to only have tried it on aryl substrates (tho I don’t see much of a reason why it should fail on an alkyl substrate in this case).
I agree on the potential problem regarding the instability of the starting chloride, but I don’t think it’s one of those cases where it should make the process straight up impossible. The details of this concern would probably have to be figured out experimentally tho.

clearly_not_atara - 30-1-2025 at 19:02

Quote: Originally posted by bnull

Quote: Originally posted by clearly_not_atara

I like bnull's approach, at least on the side of the dienophile.

It wasn't me.

That's my great weakness, reading

Maui3 - 31-1-2025 at 00:59

I think actually I might do Niklas' approach instead, and use all the catechol I made for mass-producing dopamine, lol

.

There are just a few things I need clarified. If you don't mind, could someone please send me the new synthesis scheme with all of your changes?

Thanks a lot! :-)

Maui3 - 31-1-2025 at 05:21

I ideally want to avoid using the TiCl4, it seems quite expensive..

clearly_not_atara - 31-1-2025 at 19:52

The most practical option in terms of price and safety is almost certainly going to be NiBr2(PPh3)2. Triphenylphosphine is widely used, whereas TDAE is sort of a specialty thing, and much easier to ship than TiCl4 or Fe(CO)5. NiBr2 is easily prepared from the elements or by various kinds of salt metathesis. And in fact, the nickel complex is used catalytically. Et4NI is also used, but this is also not rare nor does it require hazmat shipping IIRC.

The downside is that the rxn is only tested on the phenacyl substrates. Our substrate is very reactive, but extrapolation is always a little risky.

Attachment: iyoda1985.pdf (233kB)
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Maui3 - 1-2-2025 at 01:07

Thanks. You mentioned a furan-deriative as well - I am a bit confused, could you send the new reaction scheme please?

Niklas - 1-2-2025 at 02:21

Here would be a complete scheme of things (left in both potential diene paths), instead of the McMurry addition-elimination sequence for the dienophile I came up with an alternative approach going via the hydrazone of the corresponding diketone and eliminating with HgO.
For the 1-ethoxybutanone precursor I thought of an approach resembling the Nugent-homologisation using ethoxide as a nucleophile rather than the classic chloride (the sulfur species should be available from methyl iodide and DMSO followed by treatment with base).

Maui3 - 1-2-2025 at 04:25

Thanks Niklas - that's a really big help!

For the 1-ethoxy-2-butanone, I really do not want to work with methyl iodide, do you think there could be another way to make it - that also uses accesable starting materials? I have played around in ChemDraw for a while now, but somehow can't find a way :/. Maybe something starting from glycolic acid, acetic acid or chloroacetic acid? I have *too much* ethyl bromide on hand, so I would love to use that, if possible

Secondly, for the hydrazine part, could I use an alternative to HgO? I really do not want to work with mercury compounds either.

Oh, also, how would you make the isohexanoic acid? It's quite hard to find where I have looked, or very expensive - like 25 mL = 80 €.

Again, thank you for you help in explaining this to me!

Niklas - 1-2-2025 at 13:57

One alternative tho longer approach I would have in mind for the 1-ethoxyburanone would be to start from acetonitrile, monobrominate in GAA, make the ethyl ether by reaction with sodium ethoxide (would likely have to use two equivalents as the product would quickly get deprotonated), and then react with the Grignard reagent of ethyl bromide, what should selectively result in the ketone as nitriles have no way of reacting twice.

For the isohexanoic acid a classic Grignard approach using CO2 is probably best, this would take you back to isopentyl bromide which itself is available from the cheap alcohol by reaction with HBr.

Regarding alternatives for the alkyne synthesis I‘ll have to look through some literature, it is worth noting out tho that the HgO in the proposed path is only catalytic (the diphenylacetylene synthesis on Orgsyn uses 2-4 g for 0,5 mol), so it’s not like you would have to handle equimolar quantities of mercury salts, but yeah getting around its use is definitely still preferable even if one has the capabilities to handle and dispose of it.

[Edited on 1-2-2025 by Niklas]

Maui3 - 2-2-2025 at 02:04

Thank you Niklas!

So would our approach be something like this?

It's quite a few steps longer, but do you think still it's plausible?

If it is theoretically possible, this method is also quite cheap for me:

Acetonitrile = 6 EURO
KMnO4 = 3 EURO
TPP = 6 EURO
NiBr2 = IDK?sulfate?

That is excluding CO2, which I do not really know where to find cheaply.

Can Nickel chloride be used instead of the bromide? The bromide is quite hard to find even on chemical websites, too.

[Edited on 2-2-2025 by Maui3]

Niklas - 2-2-2025 at 02:49

The CO2 would go directly to the carboxylic acid, you can simply generate it from sodium carbonate and sulfuric acid or add it as dry ice. Other than that it looks about right, haven’t seen that kind of coupling of the carboxylic acid to the alkene before, but if you put it there I presume you found it somewhere in literature so nothing wrong with that either.

I doubt nickel chloride would work nearly as well, but I guess you could simply make NiBr2 from bromine and nickel metal as you need Br2 for some of the other steps anyway.

Maui3 - 2-2-2025 at 03:17

When you say the coupling of the carboxylic acid to alkene before, do you mean this?

Clearly_Not_Atara said this "The most practical option in terms of price and safety is almost certainly going to be NiBr2(PPh3)2. Triphenylphosphine is widely used, whereas TDAE is sort of a specialty thing, and much easier to ship than TiCl4 or Fe(CO)5. NiBr2 is easily prepared from the elements or by various kinds of salt metathesis. And in fact, the nickel complex is used catalytically. Et4NI is also used, but this is also not rare nor does it require hazmat shipping IIRC." so I understood that as TPP and Zn could be used instead of the TiCl4. I might have misunderstood it.

Also, for the grignard reagents.. I do not have argon or nitrogen, and it is very expensive where I live. How sensitive are they really? I am a bit nervous that that will make my project fail :/

[Edited on 2-2-2025 by Maui3]

Niklas - 2-2-2025 at 03:57

Quote: Originally posted by Maui3

I think that was purely referring to the coupling of the 1-bromo-1-ethoxybutanone to the furane intermediate. But yeah I‘ll see what else I can find for this type of conversion then.

Regarding the sensitivity of Grignard reactions, the main problem is generally moisture, and while they do have some oxygen sensitivity as well, as you are using really volatile diethylether as the solvent this more or less creates a blanket for the reaction mixture, so it’s generally doable without argon. Just make sure to properly dry the solvent and all the reagents beforehand, heat out the apparatus with a heatgun before adding the reagents, and attach a drying tube to things.

Maui3 - 2-2-2025 at 04:30

Quote: Originally posted by Niklas

But yeah I‘ll see what else I can find for this type of conversion then.

Again, thank you so much! You are a big help! :-)

Quote: Originally posted by Niklas

Regarding the sensitivity of Grignard reactions, the main problem is generally moisture, and while they do have some oxygen sensitivity as well, as you are using really volatile diethylether as the solvent this more or less creates a blanket for the reaction mixture, so it’s generally doable without argon. Just make sure to properly dry the solvent and all the reagents beforehand, heat out the apparatus with a heatgun before adding the reagents, and attach a drying tube to things.

Gotcha! Will do, then.

Are you at all concerned with the amount of steps in the procedure - and how much can fail lol? I mean I can get a lot of the starting materials, so I can try it multiple times, on a smaller scale, until it works.

[Edited on 2-2-2025 by Maui3]

bnull - 2-2-2025 at 08:06

Poking my nose in here again.

Treat the procedure not as a multi-step synthesis but as a series of independent syntheses whose products you intend to use later. Each product would be a goal in itself. It may seem the same thing but there are differences. The most important seems to be on the pressure that you may not feel but there always is about failure. Botching one attempt won't doom the rest.

If a product from a step is stable, keeps well etc., then the synthesis of this product is an independent procedure and you should make enough of it for the next procedure. If the product degrades or polymerizes or rearranges itself on storage, then this product is an intermediate in a more complex procedure. Once you're satisfied about the conditions, yield, side-reactions, go to the next procedure.

Edit: It looks like programming.

You're not in a sort of "Fieser's Martius Yellow Challenge", are you?

[Edited on 2-2-2025 by bnull]

Maui3 - 2-2-2025 at 08:39

Thank you bnull - those are some really good points!

I think that I didn't treat each product as a goal in itself, but the way you suggest sounds like a lot better way to do it. I'll keep that in mind from now on!

I geuss: once you successfully synthesize one product, it opens up even more ways to go about the total synthesis, than if you couldn't synthesize that product.

For each step I will probably update you all on here! Even when it doesn't work - I can hopefully get some tips.

Maui3 - 3-2-2025 at 03:15

Niklas, if you can't find an alternative to the TiCl4, maybe we could go back to this way of making it:

I will buy some sodium anyway for this.
I don't have or want to own hexavalent chromium compounds, but I will buy some potassium permanganate, if that can be used.
And I have some hydrazine.
I just don't have the HgO, and TMSCl seems very expensive.

The reason I choose the other route first was because it was quite short.. but no worries if we can't find a cheap and accesable alternative to TiCl4.

Niklas - 3-2-2025 at 11:15

One last idea I would have I somehow forgot about before would be to make isoamylbromide, and then try alkylating acetylene with it using something like sodium amide as the base and maybe ethylene diamine as the solvent (suggesting this rather odd solvent choice as alkylations of acetylene are typically done in liquid ammonia, and just like it’s fine to use EDA for Birch-reactions I guess it may work here as well).

Maui3 - 3-2-2025 at 11:38

Thanks!

It is a good idea, but I think it is a bit difficult for me too. I looked at some threads on here, and found that the TiCl4 can be made.. somewhat easily. So I think I'll try that.

Thank you for your help! I hope it's okay that I update you guys on my synthesis on here.

Niklas - 3-2-2025 at 13:11

Yeah of course!
Yeah simply making TiCl4 is ofc the other option (Thyzoid should have a video on it), I recommend complexing it with THF right after making as the resulting adduct is a lot less sensitive and just generally nicer to handle, and still works perfectly fine for McMurry reactions (as you generally us THF as the solvent it gets formed in-situ either way).

Maui3 - 4-2-2025 at 09:35

Thank you for Niklas! Will do!