Capsazepine Synthesis

I found this compound about 2 weeks ago wile reading through whimsy, it was in a thread labelled "List of compounds that are too much of a challenge".
Anyway i saw this as a challenge and after combing through the compounds listed there capsazepine stuck out like a saw thumb.
This stuff looks waaaaaaay to fun to not at the very least discuss the preparation for but please don't give me any shit like "why don't people post practical procedures and do some real lab work instead of just coming up with theoretical preparations, i miss the old days when SM members spent more time in the lab than in front of the computer".
Because this stuff is really hard to make and also as i will highlight extremely dangerous at some points so their aint no way in hell im gonna try preparing it without first running through the practical implication with you guys first and even then im not sure if I am gonna make it any time soon as much as id love too.




Anywhooo My idea was to start from pyrocatechol obviously followed by protection of the dihydroxy groups in order to carry out a grignard reaction, to protect the dihydroxy groups i would propose either williamson with dihalomethane to prepare 1,3-benzodioxol or williamson with iodomethane to prepare 1,2-dimethoxybenzene followed by bromination with n-bromosuccinamide.
The reason i suggest benzodioxol over dimethoxybenzene is because from what i understand demethylation of vanillan is an absolute bitch and demethylation of benzodioxol is as simple as refluxing in a strong acid such as HBr or HCl but id like to hear you guys thoughts on this?

Once the bromide is prepared and dried it would then be reacted with magnesium turnings in diethyl ether or THF to prepare a grignard reagent, this grignard reagent would then be filtered and put into an addition funnel and dripped over 2-bromo nitroethane followed by acidic work up in the usual fassion to prepare 3,4-methylendioxy-phenyl-2-nitroethane or 3,4-dihydroxy-phenyl-2-nitroethane.
Which ever was prepared would then need to be demethylated to reform the dihydroxybenzene followed by reduction of the nitro group using either thiourea dioxide or sodium dithionite or catalyst/hydrogen, Id recommend thiourea dioxide simply because of ease of use and availability despite never having used it myself.
The 2-bromo-nitroethane could be prepared by bromination of 2-nitroethanol which may again be prepared by the reaction of formaldehyde and nitromethane.

https://de.wikipedia.org/wiki/2-Nitroethanol
http://www.orgsyn.org/demo.aspx?prep=CV5P0833

The next compound gives me pause as its a short chain thiol.
This compound is 3-hydroxy-1-propanethiol which sigma has named 3-Mercapto-1-propanol:
http://www.sigmaaldrich.com/catalog/product/aldrich/405736?l...
I unfortunetely have no idea as to how potentially dangerous this compound is to handle but i have an idea for its preparation. First reacting allyl alcohol with HBr to get allyl bromide then reacting allyl bromide with sodium hydrosulfite to prepare allyl thiol which could then be reacted with HBr in the presence of peroxide in a reverse markovnikov to get both 2-bomo-1-propanethiol and in higher yields the desired 3-bromo-1-propanethiol, Sigma says the bp of 3-Chloro-1-propanethiol is 145*C and so the bromide should be a few tens of degrees higher, The 2 and 3 bromo propanthiols could be hopefully separated via simple distillation, fractional might be necessary but i personally have never tried fractional distillation at those kind of temperatures.
Sodiumhydrosulfite however can be prepared by reaction of hydrogen sulfide with sodium alkoxide, Scary.
http://www.sigmaaldrich.com/catalog/product/aldrich/c68601?l...

Once the 3-bromo-1-propanethiol and 3,4-dihydroxyphenyl-2-ethylamine is prepared neucliophilic alophatic substitution between both componants while keeping the bromide at an excess in order to limit di and tri alkyation.
The unreacted amine and the di and tri alkylamine would then have to be separated although their shouldn't be to much to separate if done carefully enough, since distillation is out of the question for these kinda compounds i suspect liquid layer chromatography will have to be employed

The next part is where it get interesting.

https://www.heterocycles.jp/newlibrary/payments/form/00401/P...

This would employ a pummerer rearrangement to close the ring followed by reduction of the thiol using nickel chloride and sodium borohydride to close the benzazepine and yield 5,6-dihydroxybenzazepine
Unfortunately i think this may also yield 4,5-dihydroxybenzazepine but i don't have access to the paper.

Ok now this is where things get difficult, we need to substitute the amine with thioamide and i can only find 3 ways of doing this first is the kindler thioamide synthesis which would have to probably follow N substitution with acetyl chloride.
http://www.organic-chemistry.org/namedreactions/willgerodt-k...

The next method used a rather difficult to prepare reagent called the lawesons reagent or possibly phosphorous pentasulfide, by reacting either of these with the preprepared carbamide which im still a little iffy on how to prepare and also combined with the general un availability of lawsons reagent im not really gonna go into this method.

The third looks most promissing but also the most dangerous, it involves N substitution using cyanogen bromide and then proceeding in a similar manner as to how thiourea is prepared:

https://en.wikipedia.org/wiki/Thiourea

The LiAlHSH should not be too difficult to prepare provide LAH is on hand and cyanogen bromide can be conviently prepared by reaction of bromine with sodium cyanide.
NaCN + Br2 ---> BrCN + NaBr
https://erowid.org/archive/rhodium/chemistry/eleusis/cnbr.ht...

This leave us finally with the preparation of p-chloro phenyl-2-ethylbromide,
My idea for this was again simple, starting from styrene followed by chlorination with ferric chloride under dry conditions followed by distillation. Bp of p chlorostyrene is 192*C
http://www.chemspider.com/Chemical-Structure.13465.html
Bp of o chlorostyrene is 189*C
http://www.chemspider.com/Chemical-Structure.14205.html
For separation of the ortho and para isomers i recommend taking advantage of sterric hinderance in the same way that nerdrage did in his separation of chlorotoluene video only at much higher temperatures, around 200*C maybe a bit higher in a dean stark set up, hopefully they don't decompose to much at these temps.

The other much more lengthy method would be para nitration of styrene using acyl nitrate in zeolite:
http://www.sciencedirect.com/science/article/pii/S0167299199...
This p-nitrostyrene would then have to be reduced to an amine followed by diazatization with sodium nitrite and then finally reaction with copper chloride to get p-chlorstyrene.

The p-chlorostyrene could then be reacted with HBr in the presence of a peroxide again in a reverse markovnikov to get a mixture of phenyl alpha and beta brominated substrates, however im pretty sure phenyl-alpha-bromoethane undergoes hydrolysis to yield phenyl-alpha-hydroxyethane which would make separation considerably easier, possibly simple distillation if we can find the bp of p-chlor-phenyl-alpha-hydroxyethane.
https://www.alfa.com/en/catalog/A16839/

Then to finally arrive at our final destination neucliophilic alophatic substitution of p-chloro-phenyl-beta-bromoethane with N-thiourea-5,6-dihydroxybenzazepine wile keeping the benzazepine in excess to yield Capsazepine.

You don't specify as to how you would form the benzazepine ring from the phenylpropylamine so im assuming this is specified in the reference you gave, i unfortunately don't have access but i will put a request in References.

Thanks for all your replies.

Alice this might help

I was having issues uploading the photos from my camera, for some reason they registered as being to big but i have managed do this using my phone so apologies for the bad quality, also I don't have much light so they arn't the easiest to read.
This is my origional idea however i haven't drawed out the route to the p-chloro-phenyl-2-bromoethane.

I skipped drawing out the reduction of the nitro group and the deprotection/demethylation of the diol.

I will try drawing out the route suggested by CuReUS soon.

Again given recent posts this method wont work, however it may work if we were to replace the grignard between the bromobenzene and 2-bromo-nitroethane with possibly a mannich reaction between catechol ammonia and formaldehyde however im not sure if this would be specific enough to just alkalate the desired position and we may end up with 2,3-dihydroxy-phenylmethylamine as a side product.

Assured Fish, thanks for the pics. Now as you can see, in the second pic, there is a carbon vanishing.
For drawing such schemes, either use the chemdraw trial version or the ChemSketch freeware.
For the bromination, NBS is not OTC, but as this is an activated arene there is a vast number of halogeation reactions available. Br2 being one of them or just in situ generated Br2.

Yes, either there is a concerted elimination of HBr or the negative charge is resonance-stabilized by the nitro group before elimination happens. See Henry reaction where deprotonation is intended in order to generate a nucleophile. Bromonitromethane won't solve the problem either as it's deprotonated too.

For the next step the reagent you suggest is 3-bromopropane-1-thiol. This will also react with itself and reacts twice with the benzylamine, as such a reaction would be performed with an auxiliary base, otherwise HBr formed blocks benzylamine for further reaction or may deprotect the phenolic groups. A short search reveals for such reagents the thiol is often protected as thioacetate.

For the other routes, CS2 isn't the only problem. For the other reactions stuff like phosgene, diborane, TiCl4, ethyl chloroformate, NaN3, POCl3, trichloroacetic anhydride, and TEMPO are required. Reagents difficult to make or pretty much dangerous to handle. This is hardly pratical and for being OTC something more straight forward and easier would be nice.

Additionally, the most crucial part for all of these reactions isn't the reactions themselfes or the various reagent preparations, but how to purify the products and how to make sure the compounds are the compounds intended. I count about 10-11 transformations not including the reagent preparations.

[Edited on 7-5-2017 by Alice]

Quote: Originally posted by Assured Fish

I will try drawing out the route suggested by CuReUS soon.

Quote: Originally posted by Alice

For the bromination, NBS is not OTC

stop suffering from OTC OCD. .This isn't a nitrobenzene to aniline type of synthesis.Desperate compounds call for desperate measures.

Quote:

Additionally, the most crucial part for all of these reactions isn't the reactions themselfes or the various reagent preparations, but how to purify the products and how to make sure the compounds are the compounds intended. I count about 10-11 transformations not including the reagent preparations.

instead of laughing at other people's syntheses,why don't you come up with a "simple, straight forward,practical and easy route" which uses safe reagents and is 100% OTC ?

[Edited on 7-5-2017 by CuReUS]

CuReUS, I just thought that something has changed. BTW I'm not laughing at other people's synthesis at all. That was just my way expressing this synthesis isn't trivial - not bad.

Of course, with enough energy and time it's possible achieving a lot OTC, but if really nothing is available and everthing has to be prepared in one or multiple steps in a more or less complicated manner it's just getting impossible for normal people to afford the workload.

Fortunately I have indeed made my own thoughts on the problems I have named.

Here is my draft for the synthesis of the left part (benzazepine). I paid much attention making the synthesis OTC friendly using only chemicals which are either available or there are established OTC procedures for making them. I'm aware the last step (thermal cyclization) is the most critical step and may be substituted in one way or another, maybe by cleaving the benzyl ether beforehand. The preparation of 1,3-diiodopropane will take two steps. 1. Transformation of 1,3-propanediol by distillation from NaCl and a suitable acid into the dichloride. 2. Double Finkelstein reaction with NaI leading to Cl/I exchange.


EDIT: Forgot to provide the link for yeast mediated reduction of vanillin:

http://pubs.acs.org/doi/abs/10.1021/ed070pA155

EDIT3: Added more precise wording.


EDIT4: Update

In chemistry there is always room for optimization, a never ending story.

Possible side products of 1,3-dichloropropane (b.p. 121 °C) synthesis like allyl chloride (b.p. 45 °C) or 1,2-dichloropropane (b.p. 95 °C) will be removable by fractionated distillation, alcohols by washing the product multiple times with water. I assume removing the chlorinated products under reduced pressure during the reaction may be fortunate or even neccessary. I have chosen the chlorination over iodination or bromination because the boiling points are more practical and it's better starting with cheap stuff.

The Finkelstein reaction may be performed with just 1 eq. NaI, as the statistical yield of 3-iodo-1-chloropropane is 75%. Assuming a slight dependence on the second substituent, e.g. sterically, an even higher ratio may be obtained. This leads to a lower boiling product which might then be distilled under reduced pressure (aspirator vacuum) saving half of the sodium iodide. The Grignard will prefer substituting the iodide over the chloride while the chloride remains still reactive towards ammonia. The ammonia additon may be done one-pot, or just after removal of the salts, as it enables further acid-base extraction. At that point hopefully other side products not being an amine will be removed. A possible toxic side product is propylene-1,3-diamine which is water soluble and removed by acid base extraction.




[Edited on 7-5-2017 by Alice]

[Edited on 7-5-2017 by Alice]

[Edited on 8-5-2017 by Alice]

[Edited on 8-5-2017 by Alice]

@Eddygp. As I said I didn't suggest the last step because it sounds so promising, it would just be so interesting to know whether it works. As a temperature range I think about anything between 200 °C and pyrolysis. At least for me chemistry would become very boring if I never tried to check out where the limits are.

On the other hand the benzyl ether can be transformed into any other functional group, for example back to the aldehyde, which would give an imine then. Still easier to reduce than the lactam though. A quaternary benzylamine would be another idea.

[Edited on 8-5-2017 by Alice]

As per request, I'll attach my synthesis here, starting from vanillin and styrene.
There are two possibilities for the reduction of the oxime because I found two different methods on YouTube by competent chemists. In writing a more detailed document, I included both of these.
Also, the use of boron tribromide as the demethylation agent was chosen since there was an OrgSyn reference for that procedure, and both boron and bromine are relatively OTC.

Alice:

1. I was aware that styrene + HCl would give mainly the undesired product; I had forgotten to point that out in the post. My thinking was that since the precursors were cheap and readily available, one could obtain sufficient quantities for the main synthesis without too much difficulty. However, I appreciate the drawbacks of this idea, namely green chem.

2. Crossed-fingers

3. Not something I had given much thought to; the lecturers at my university have historically indicated that intramolecular reactions are kinetically favoured over intermolecular ones. However, your point raises another one - could it instead react ortho to the phenol instead of meta? This does form a bridged compound, however.

4. The orgsyn reference:
Org. Synth. 1969, 49, 50
DOI: 10.15227/orgsyn.049.0050
http://www.orgsyn.org/demo.aspx?prep=CV5P0412

[Edited on 8-5-2017 by 12thealchemist]

Quote: Originally posted by Alice

Fortunately I have indeed made my own thoughts on the problems I have named.

Or unfortunately,as we will soon see
First of all,any route is only as good as its references.Since you do not provide suitable references,your route fails there itself.
Now lets go through your synthesis
1.For the vanilin reduction using yeast,not everyone has a centrifuge lying around,you know.
2.You have problem using azide,but no problem using K ?Also MeI is a very safe reagent according to you ?
3.bromination will give other isomers too.Will you be able to separate them ? Also,the HBr formed as a side product might demethylate the ethers
4.Pls give a reference where an alkylation is performed using grignard alone
5.How will you prevent the formation of 2nd,3rd and quaternary amines ?
6.And last but not the least,The cyclisation you propose might work in wonderland,but it won't work here on earth

Quote: Originally posted by Alice

On the other hand the benzyl ether can be transformed into any other functional group, for example back to the aldehyde, which would give an imine then. Still easier to reduce than the lactam though.

Quote: Originally posted by 12thealchemist

As per request, I'll attach my synthesis here, starting from vanillin and styrene.

Your route is quite simple,but the problem is that in organic chemistry,simplicity and selectivity do not go hand in hand

I don't know which competent chemists you are referring to,but both the chemists I know have run into problems trying to reduce oximes using Zn.Chemplayer said that the final product was inpure and had to be furthur purified whereas nile red failed to reduce it itself.Another youtuber claims to have done it,but he got a shitty yield of 36%

2.In the alkylation step,isn't there a chance of the propane dichloride reacting twice with NH₂ to form an azetidine ?
3.Even if the FC intramolecular cyclisation went well,that naked phenol and even the NH would react with the AlCl₃ to form tar
4.Demethylating the ether before reacting it with the isothiocyanate might lead to a competing reaction between the OH and the N,as I have mentioned before

As for the other half,you will have a warm time during the p-chlorination.Just ask Nurdrage.Also the last step is wrong,since isothiocyanates are extremely susceptible to hydrolysis,and the NaOH would react with it before the benzazepine even had a chance

[Edited on 9-5-2017 by CuReUS]

Quote:

Or unfortunately as we will soon see First of all,any route is only as good as its references.Since you do not provide suitable references,your route fails there itself. Now lets go through your synthesis

Quote:

6.And last but not the least,The cyclisation you propose might work in wonderland,but it won't work here on earth

I don't share your attitude of knowing beforehand what's possible and what's not. Once I heard a lecture of a professor who said to the students: if you are done with the master, try to forget as much as possible as it will just clog up your mind.
Of course that was meant polemic but the core message is: never be too sure.

Quote:

>> Quote: Originally posted by 12thealchemist >> As per request, I'll attach my synthesis here, starting from vanillin and styrene. Your route is quite simple,but the problem is that in organic chemistry,simplicity and selectivity do not go hand in hand

Aaaaaand im late to the party.

The following scheme is what I think was origionally proposed by CuReUS starting from safrole or eugenol, however i am a little confused as to how you intended to use a modified schmidt reaction on the ketone/amide, i thought we would just want to reduce this completely using NaBH4 or LAH to get the benzazepine ring.





The formation of the benzazepine ring was taken from this reference that was sent to me from CuReUS. http://pubs.acs.org/doi/abs/10.1021/jm00039a006

Fenclonine to nitrile. http://www.sciencemadness.org/talk/viewthread.php?tid=32534

And his reference for the deprotection of the diol for which i don't have access to. http://pubs.acs.org/doi/abs/10.1021/jo9910740

I have a modification though for which i have not drawn out unfortunately.
Instead of forming the isothiocyanate from the amine using CS2 we could instead opt to convert the amine to an isonitrile using chloroform and a base which would be about as OTC as you get:

CHCl3 + NaOH/KOH -----> CCl2 + R-NH2 -----> R-NC

The isonitrile could then be reacted with sulfur like in the following reference:
http://www.organic-chemistry.org/abstracts/lit4/754.shtm

This would mean that we could do away with the CS2 and instead opt for an OTC approach using sulfur, chloroform and KOH to bridge the p-chlorophenethylamine and benzazepine forming the thiourea bridge.

Some references

Quote: Originally posted by Alice

Not getting my point isn't a reason behaving like a child as you have illustrated

I used plural because I wanted to point out the flaws in your route to others.As for the spaces,blame the site posting software,not me

that's what they use in the only ref you linked,possibly to remove the crappy yeast cells.Don't shoot the messenger

No I didn't,I got into chemistry yesterday..Also since the ring in highly activated,you will have di/tri bromination to care of too

I don't think you know how much NH₃ you would need to prevent polyalkylation if you decided to follow that primitive route.IIRC,the ratio of NH₃ to RX is 20:1 .Have fun working with that much NH₃

Quote: Originally posted by clearly_not_atara

The isothiocyanate will not react with the phenol, as phenols do not autoionize in non-aqueous solvents, so it is okay to deprotect before this coupling. I think a couple of people missed this.

actually,I had a doubt about this upthread.But since no one clarified it,I assumed it to be a potential side reaction,to be on the safer side.I am relieved that the deprotection can be done before the final coupling.It would have been a disaster to destroy the whole molecule just to take the protecting group out

Quote: Originally posted by Assured Fish

Aaaaaand im late to the party.

Man,your compound seriously heated up this thread

Brilliant drawing,but you have messed up a few steps
1.In the 2nd step,the acid undergoes an intramolecular FC acylation using TCAA to form the ketone
2.Then the modified schimdt is done on the ketone using HCl/NaN₃ to get the cyclic amide(lactam)
3.Finally,the lactam is reduced to benzazepine using LAH

As for the right half-
1.I just realized now that there is no need to convert fenclonine to the nitrile and then reduce it,it can be directly decarboxylated to the amine
https://erowid.org/archive/rhodium/chemistry/tryptophan.html
http://www.sciencemadness.org/talk/viewthread.php?tid=8574
2.The safrole is deprotected before the coupling,following atara's recommendation.
3. As I mentioned above,acetonitrile is used as the solvent in the coupling step,not toulene. Did you have any reason for using the latter ?

from the ease with which you suggest making isonitrile,its obvious that you have never worked with them.I suggest you don't,they stink to high heavens and they are extremely toxic(I got poisoned from just one whiff the first time I made them)

[Edited on 9-5-2017 by CuReUS]

@AVBaeyer

Because it was clear to me from the beginning that the available synthesis most probably would have been developed with a different focus than I think is needed in order to achieve a practical OTC synthesis. So why not trust in ones own experience and creativity and discuss that here on SM. Just grabing the literature procedure to achieve (or not to achieve) the goal by force doesn't meet my philosophy. Not to cause any misunderstandings, I'm happy having my opinion and others having their opinion, even if this is pissing in the wind for others, although sounds cumbersome to me, no offence intended.

@Assured Fish

Great drawings. If I got that right the synthesis shown in the left pic changed. The butanoic acid is activated by some activating agent and then undergoes cyclization (Friedel-Crafts acylation), then the ring is expanded by the modified Schmidt reaction.

How about the Beckmann rearrangement utilizing hydroxylamine? EDIT: The Beckmann rearrangement leads mostly to the wrong product, known at least for the non substituted derivative.

[Edited on 9-5-2017 by Alice]

CuReUS could you elaborate further or perhaps draw it out for us pretty please?

Hey I also used an intramolecular Mannich... although I severely underestimated the difficulty of reducing Cp2ZrCl2, which it turns out can pretty much only be done with aluminium hydride reagents. The best route I found so far uses DIBAL, which can be made OTC (or some similar replacements) but is well worth avoiding.

I think that you could actually get away with performing the radical addition of HBr to safrole. As long as the conditions are nonpolar enough, Br- ions won't be present, and the ether won't be protonated, which means it won't be cleaved. Probably benzene is the best solvent since I'm not sure how well safrole will dissolve in hexane. I'm also not sure what the best radical initiator is, but you can make something like AiBN by making butanone azine the usual way and converting the hydrazones to tetrahedral carbon atoms with a carbanion like ethyl acetoacetate. Or tert-butyl peroxide might be accessible somehow but I have no idea. I think methyl iodide and ultraviolet light counts as a radical initiator in some jurisdictions.

From there you can staple on the amine of your choice or potassium isocyanate if for some reason you actually want to use isocyanates like some people in this thread.

Actually it's possible that if you try to perform the Delepine on the benzodioxol-5-propyl bromide you'll end up forming the azepane because the transient iminium will attack the arene rather than being hydrolysed by water. It might even be possible to "force" this reaction by decomposing the hexamine onium with acid in the absence of water. This would be a particularly elegant approach if it worked:

EDIT: LOL there's an extra "N" in there somewhere, stupid drawing software



[Edited on 10-5-2017 by clearly_not_atara]

Here is another draft, applying some changes, especially four points mentioned by clearly_not_atara, which is avoiding K, avoiding ether at least in one step, acetal protection, and applying the Delépine reaction.





EDIT: Revised route.

Not sure about the Leuckart-Wallach and maybe the formaldehyde formed in the Delépine reaction may lead to some unwanted side reactions, which may be circumvented by using the Gabriel synthesis or succinimide as the amine donor. EDIT: Buffering the bromination may be neccessary in order to save the acetal from deprotection.

[Edited on 10-5-2017 by Alice]


@Assured Fish

Quote: Originally posted by Dr.Bob

But the Lee route to the azepine seems more doable for OTC possibilities,So I would favor the Lee routes so far. the Lee route could be the best way to start.

Quote: Originally posted by clearly_not_atara

The best route I found so far uses DIBAL, which can be made OTC

You know how to make hydrides at home ?

Quote: Originally posted by Assured Fish

Im inclined to agree with Dr.Bob, the lee ref using an intramolecular Mannich from phenylpropylamine kinda trumps most of the overly complicated routes any of us have suggested so far.

That's where you are making a mistake.The cyclisation won't give you the azepine directly,it will only give the ketone.You will have to then convert the ketone in 2 steps(modified schimdt followed by reduction) to the azepine.
I am attaching a pic of the route.As for the cyclisation mechanism,Alice has hit the nail on the head and explained it beautifully.

Quote: Originally posted by Alice

On the other hand I guess if both methoxy groups are cleaved beforehand the Mannich also happens in ortho-phenol position.

Not to mention the crap formed by the reaction of HCHO with the diol

[Edited on 10-5-2017 by CuReUS]

Here is my third draft, reintroducing the yeast mediated reduction of vanillin and K for its global deprotonation. Not sure but would be fortunate if KOH works instead. A method for the extraction of vanillyl alcohol is required, which doesn't end up in a mess and too much chemistry in buckets. EtI is introduced in order to avoid MeI. The second last step may be omitted which may reduce the synthesis to 7 steps (not counting reagent prearations). Although I suspect the resulting product will have a higher purity going for the quarternary ammonium salt, hopefully making intermolecular reactions especially between the amine and the benzyl bromide less likely.

Trimethylamine may be obtained by treatment of any available quaternary trimethyl ammonium salt with a strong base like KOH. In this synthesis a global deprotection (hopefully leading to the benzyl bromide intermediate) was chosen, avoiding an extra step for the aryl ether deprotection. I would not recommend isolating the bifunctional amine/bromide, just boiling off the HBr, adding it to a new solvent containing trimethylamine. Something which wasn't discussed before but I think is imporant to know is the deprotection utilizing HBr will yield bromoalkyls, so be aware of the gases formed.

Quote:

Not to mention the crap formed by the reaction of HCHO with the diol

Different types of resin.

[Edited on 11-5-2017 by Alice]

[Edited on 11-5-2017 by Alice]

Quote: Originally posted by Alice

The second last step may be omitted which may reduce the synthesis to 7 steps

@JJay, the brand mentioned in the paper is Fleischmann's "active dry" yeast. I don't know this particular brand but it looks like usual baker's yeast. There are lots of publications focusing on yeast mediated reducion of ketones especially aryl alkyl ketones. I didn't know before it works for vanillin too. I didn't find much about aldehydes. If you are interested, did you know carrots can be used as well for ketone reductions into chiral alcohols?
That might be interesting for vanillin reduction too.

[Edited on 11-5-2017 by Alice]

But if you don't free base it,the NH₂-Br salt won't react with the benzyl bromide.Also,I just remembered that catechols get oxidised very fast in the presence of base,so the free-basing step is a necessary evil

Quote: Originally posted by JJay

I find the notion that baker's yeast can do reductions to be fascinating.

Quote: Originally posted by JJay

Wow, that is pretty much the most garden variety of yeast I can think of. I actually have a stray packet of it sitting around here somewhere.

Quote:

But if you don't free base it,the NH2-Br salt won't react with the benzyl bromide.Also,I just remembered that catechols get oxidised very fast in the presence of base,so the free-basing step is a necessary evil

I’ve seen this thread pop up more than once in today’s posts over the past weeks and have given the idea some thought.

First off I will go through this without any of the OTC fetish and establish the general scheme. Later I will comment on certain steps and suggest possible OTC alternatives. If you have any additional suggestions, blast away!

So I´d start from catechol and suitably protect this with some alkyl groups. Compound 1 would be then be subjected to Friedel-Crafts acylation with succinic anhydride. After separating the other possible isomer of 2, 2 would be subjected to a Curtius rearrangement in which the heating step would be performed in an anhydrous environment. This would hopefully give the isocyanate, which upon treatment with anhydrous acid would cyclisize to form 3. Reduction/deoxygenation under harsh conditions should furnish 4 which would be deprotected to 5 by refluxing in HBr.

Then onto the p-chlorophenethylamine isothiocyanate. Ring chlorination, radical benzylic chlorination and substitution with a cyanide salt as per NurdRage. Then reduce 8 with alane (fearing loss of the ring Cl when using straight LAH). Activation of 9 with thiophosgene should allow it to be attached to 5 and yield capsazepine.

Overall I think it is pretty atom efficient except for the steps where isomers can be formed: 12, 23 and PhMe6. I've looked in reaxys and most reaction are known, although not for the particular compounds. Having said that I'm sure I could provide credible references on most reactions if It weren't for me closing all the tabs and discarding the information last night.


The main problems for OTC style would be Curtius&cyclization 23, reduction 34, reduction 89 and 910.

23: instead of using DPPA or SOCl2 then NaN3 one could use TCCA to make the acid chloride and then make the acyl azide. Isolate that and heat it in anhydrous conditions to give the isocyanate.

34: Somewhat more problematic but possibly HI/Red P could work, although I have my doubts about reduction of the amide. These conditions may even do a tandem demethylation making it 35

89: May be achieved by aluminium amalgam reduction. There are plenty of routes to phenethylamines.

910: The reason why I think this is not an OTC style synth. and it is not worth bothering starting from absolute schratch. Although conceivably it is possible from C/SCS2 + Cl2 CSCl2

CuReUS, I think boiling 48% HBr isn't exactly a very good hydrolytic condition. In the following I show you what I'm afraid might happen.

Quote:

But if you don't free base it,the NH2-Br salt won't react with the benzyl bromide.Also,I just remembered that catechols get oxidised very fast in the presence of base,so the free-basing step is a necessary evil

Quote: Originally posted by Assured Fish

It is possible for us to freebase a quarternary ammonium salt without using strong bases which might react with the catechol.

The salt I am referring to here is a primary amine salt,not a quat

Quote: Originally posted by Sigmatropic

This would hopefully give the isocyanate, which upon treatment with anhydrous acid would cyclisize to form 3....

both the refs I found on FC acylation using isocyanate use BF₃.Et₂O
https://en.wikipedia.org/wiki/Curtius_rearrangement#Dievodia...
http://pubs.rsc.org/en/Content/ArticleLanding/2014/QO/c4qo00...

Quote: Originally posted by Sigmatropic

34: Somewhat more problematic but possibly HI/Red P could work, although I have my doubts about reduction of the amide.

HI/red P would break the lactam

Quote: Originally posted by Alice

CuReUS, I think boiling 48% HBr isn't exactly a very good hydrolytic condition. In the following I show you what I'm afraid might happen.

what other context is there for free basing ? That's what it means in all contexts.

[Edited on 13-5-2017 by CuReUS]

Both isn't completely impossible, so I wouldn't exclude any possibility. Especially the esters may be activated by HBr and undergo acylation. If esters form, although it's reversible, it wouldn't solve the goal omitting a step, especially a polyester would be unfortunate.

Quote:

what other context is there for free basing ? That's what it means in all contexts.

I have explained what free basing means in general just in the previous paragraph. Context in this context means the molecule we're talking about. But I'm pretty sure you know how it was meant.

@AvB. Sorry for the late answer, I was busy. You are speaking very indirect and general, so I have no clue what you're talking about. Do you think I don't have a sound understanding of organic chemistry or do you think someone having no sound understanding of organic chemistry should do this and that instead of thinking about new total synthesis? Do you think I don't know anything about total synthesis or are you explaining total synthesis in general? Do you think I should utilize standard reactions or do you think others should utilize standard reactions? How would you define standard reactions and what would be non standard reactions then? If this happens to be a controversy, I'd like to know what's your point.

I took a different path - as a conscious decision. Anyone can choose whatever exercize this may be. You named another one, more beginner friendly perhaps. As I tried to explain you before, you can either choose to develop OTC reagent synthesis for known routes or you can develop a route according to OTC reagent availability. Both has it's own charm, but there is no such thing like right and false here.

[Edited on 14-5-2017 by Alice]

[Edited on 14-5-2017 by Alice]

Quote: Originally posted by Alice

But I'm pretty sure you know how it was meant.

No I didn't,I swear.In fact,I feel like an idiot now for asking such a stupid question

Quote:

Both isn't completely impossible, so I wouldn't exclude any possibility. Especially the esters may be activated by HBr and undergo acylation. If esters form, although it's reversible, it wouldn't solve the goal omitting a step, especially a polyester would be unfortunate.

Quote: Originally posted by CuReUS

Quote: Originally posted by Alice   But I'm pretty sure you know how it was meant. No I didn't,I swear.In fact,I feel like an idiot now for asking such a stupid question:

I honestly thought you were just kidding me.

Sorry i misunderstood what alice wanted to do with that reaction.
I must admit you guys tend to loose me alot in this thread, i feel like the fumbling bafoon trodding along after you guys with pockets full of stones

Quote: Originally posted by Alice

Possibly adding sodium succinimide after the grignard one-pot would safe a work-up.

Quote: Originally posted by Assured Fish

although CS2 is a bitch to make.

just buy it,for chemistry's sake

Quote:

I must admit you guys tend to loose me alot in this thread, i feel like the fumbling bafoon trodding along after you guys with pockets full of stones

Just a matter of practice and experience.
There are just so many things you don't think about if you don't have much experience (or a bad day ). That's normal.

Quote: Originally posted by CuReUS

isn't there a chance that some of the unreacted dihalopropane might also react with the succinimide ?

Sure, but 1,3-diaminopropane is soluble in water while the product amine supposedly isn't. And it has reportedly a logP_ow of -1.3 (wiki, not sure if this is calculated), which means it prefers the aqueous phase as the free base. Recrystallizaton of the substituted succinimides may be another way separating it.

Here is a paper introduced showing a modified Grignard adding 3 mol% anhydrous CuCl2 in THF. Examples are:

p-methoxyphenylmagnesium bromide (1.2 eq.) with octyl bromide (1 eq.): 97% yield

p-dimethylaminophenylmagnesium bromide (1.2 eq.) with 1-chloro-5-bromopentane (1 eq.): 93% yield

With a bit of luck this works good as well with diethyl ether and the two possible reagents 1,3-diiodopropane and 1-chloro-3-iodopropane. CuCl2 is about the most trivial additive I can think of and 3 mol% looks great.

[Edited on 15-5-2017 by Alice]

EDIT:

confused edit removed

[Edited on 15-5-2017 by Alice]

p-chlorophenethyamine prep?

Ok so ive been searching around for a source of fenclonine and have found nadda, its like this stuff is a prescription med or something even though all the sources ive read on the stuff don't refer to it being prescription based.

So i propose a different route to synthesize pCPEA (p-chlorophenethyamine) based of the same concept but starting from phenylalinine.

The decarboxylation is still the same as the one previously proposed by CuReUS here:
https://erowid.org/archive/rhodium/chemistry/trp.decarbox.en...

Then selective para-chlorination using potassium peroxymonosulfate (oxone) as a catalyst and KCl in acetonitrile.
https://erowid.org/archive/rhodium/chemistry/oxone.aromatic....

The only thing is I don't have direct access to the product Oxone, but i have found a product that contains peroxymonosulfate on ebay that looks like oxone:
http://www.ebay.com/itm/saltscapes-chlorine-free-oxidizer-sh...

Also a source of phenylalinine that's pretty cheap: http://nootropicsdepot.com/dl-phenylalanine-powder/

Quote: Originally posted by Assured Fish

Ok so ive been searching around for a source of fenclonine and have found nadda, its like this stuff is a prescription med or something even though all the sources ive read on the stuff don't refer to it being prescription based.

Two new drafts for the second part, the first for p-chlorophenylethyl halogenide the second for p-chlorophenylethylamine. I dont suggest any specific chlorination for now, nor do I comment it, at least for now.






EDIT:

After I had a closer look at the first suggestion, it's a bit overcomplicated, so I made another draft:



The first step is taken from the literature, where NaBr is used (90% yield for phenylalanine). I speculate NaBr may be substituted by NaCl which hopefully works too. For the chlorination the procedure posted by Assured Fish may work good here, a closer look at the original publication reveals for isobutylbenzene yields of 72% para, 2% ortho, and 1% disubstitution (75% conversion). Fairly good! The substitution performed by AgCN is described in the literature, but I have to find a good source first. The decarboxylation hopefully works freely as known for similar structures. The literature source for the last step is described in my previous post and can be found here.

[Edited on 16-5-2017 by Alice]

[Edited on 16-5-2017 by Alice]

[Edited on 16-5-2017 by Alice]

Yusss someone else thinks the isonitrile is a better route than CS2, try telling CuReUS that; he thinks we're mad.

Edit: just realised that phthalamide would also be chlorinated so succinimide is really the best option.

[Edited on 17-5-2017 by Assured Fish]

[Edited on 17-5-2017 by Assured Fish]

Quote: Originally posted by Assured Fish

@Alice Thanks for the correction, looks like a protecting group of succinimide/phthalamide is the best way to go about it then and it could still be accomplished in 2 pots.

Quote:

Quote: I was looking for a few possibilities avoiding CS2. The first couple of options involve the transformation of isonitriles into isothiocyanates by different catalysts with elemental sulfur: Yusss someone else thinks the isonitrile is a better route than CS2, try telling CuReUS that; he thinks we're mad.

We're all mad here...

Probably not, as it's deactivated. The authors of the paper you referred to (KCl-Oxone system) didn't find any chlorinated product for benzoic acid for example.

Here is the 4th draft assuming there is no need for amine protection other than protonation. The first two steps may be done the other way round, additionally the second popular isocyanide formation reaction is shown, avoiding AgCN:




EDIT: As an additional note: THF utilized in the last step may be substituted by diethyl ether or dioxane making this reaction more OTC.

[Edited on 17-5-2017 by Alice]

[Edited on 17-5-2017 by Alice]

[Edited on 17-5-2017 by Alice]

Quote: Originally posted by Alice

Selenium and especially tellurium are easy to aquire OTC as far as I see.

really ?

Quote: Originally posted by Assured Fish

I also am pretty sure hunsdicker has trouble proceeding on saturated alkyl carboxylates

Quote: Originally posted by Assured Fish

Yusss someone else thinks the isonitrile is a better route than CS2, try telling CuReUS that; he thinks we're mad.

isonitriles and Te.What a wonderful combination to stimulate one's olfaction. spring is going to come early for some this year

[Edited on 17-5-2017 by CuReUS]

Quote: Originally posted by CuReUS

Quote: Originally posted by Alice   Selenium and especially tellurium are easy to aquire OTC as far as I see. really ?

As I didn't mention this before, in my first route draft where I suggested cyclisizing the amine directly with the benzyl ether, displacing methoxide, it caused quite some doubts about how this might be possible. This idea came to me as I remembered having read a paper about the synthesis of levetiracetam (An alternate synthesis of levetiracetam) in the past and thought about if there is a possible cut through for the present synthesis. For some instances the case differs, but for others it doesn't, which I will explain in the following.

For the levetiracetam synthesis, 2-aminobutanol is reacted with gamma-butyrolactone whereas in the first step aminolysis with ring opening occurs resulting in an amide. Then the amide-N acts as a nucleophile and substitutes the hydroxy group. The first step isn't really sursprising, while the second one would probably not have been expected. It becomes more clear as in a former synthesis 4-chlorobutyryl chloride was utilized instead of gamma-butyrolacton, a much more expensive and hazardous reagent. The reaction is performed at different temperatures, 160 °C (8 h, 76% yield, 5 mol% H3PO4 as catalyst) and 225 °C (10 h, 93% yield, no catalyst) solvent-free. Additionally the reaction can also be enhanced by microwave irradiation providing lower temperatures and greatly reduced reaction times (1 h, 200 °C, 82% yield). The reaction works because five-membered ring formation is favored (Baldwin's rule), it even outperforms hydroxide being a bad leaving group and an amide being a bad nucleophile.

For the reaction I suggested, a less kinetically and less energetically favored 7-membered ring is proposed to form and the less favorable methoxide as the leaving group. Nevertheless, two out of six angles are sterically fixed, making the 7 membered ring already partially in place, the benzylic position is activated for substitution compared to an aliphatic position, and the amine is a good nucleophile. An interesting effect known for benzylic substitution reactions is the dependence of rate constants on aromatic substitution pattern. While EDGs in para and ortho position enhance reaction rates, destabilizing the bond between benzylic carbon and substituent and stabilization of the transition state. EWGs show the opposite effect. (See: Kinetics and Mechanism of the Pyridinolysis of Benzyl Bromides in Dimethyl Sulfoxide or https://books.google.com/books?id=AgU4AAAAIAAJ&pg=PA134).

As I mentioned before my suggestion is, in my opinion, a very experimental suggestion, but didn't come from nowhere. The only question which matters for the proposed reaction is if it proceeds in a considerable speed before pyrolysis occurs. H3PO4 or microwave probably wouldn't hurt too

[Edited on 21-5-2017 by Alice]

Quote: Originally posted by tsathoggua1

Having looked up fenclonine, I can more or less guarantee that, short of third-world or countries where pharmacists are bribable for more or less anything if somebody has the money, given its action that isn't a drug that is going to be OTC.

why do you want to buy it from a brick and mortar shop,you could just order it online.Don't tell me you take the literal meaning of the word OTC

Quote: Originally posted by Alice

Seems like I don't get the point. What's the problem with chlorinating 1,3-propanediol by NaCl/H3PO4 followed by Finkelstein reaction?

Curious-guilty as charged, in that instance. Thats having a literally-inclined mind for you, it does that sometimes and realizes later

That, and I am not sure how much I trust online pharmacies, particularly ones I haven't in the past done business with. There are certainly plenty of skeezy thieving scumbags around, its just the sort of business that attracts such vermin like shit draws flies.

Also, whilst I don't know for sure, it looked like the kind of thing that might not survive the test of time, with regards to being in current use or not, owing to the discontinuation of para-chloroamphetamine, which, unfortunately, was used as a diet drug, until it was realized that the non-fluorinated para-halogenated amphetamines (and presumably para-cyano/4-nitro also) are seriously bad news and produce potential permanent or very very long lasting depletion of tryptophan hydroxylase. Although at least, the phenethylamine homolog might prove to be a better substrate for MAO-a without the alpha-substituent.

Didn't stop some bloody stupid and reckless online grey market vendors marketing para-bromo(meth)cathinone for some time, though. Which if its still around, could be an alternative with reduction of the ketone and finkelstein reaction, if an alpha-methyl substituent (using the nomenclature for numbering of phenethylamines and amphetamines) would produce an analog of capsazepine active at TRPV1 receptors.

As for the propadiene, its sold in my part of the world (UK of all the shitheaps) for use in welding. I hadn't realized about the equilibrium, or at least, wasn't sure how fast they would interconvert and had thought to distill it under a freezing mixture (or rather, let it distill itself, without external applied heat), the propyne in MAPP gas would come off first.. How fast do they interconvert? and what are the numbers like for the relative proportions of propyne and propadiene at RT and in the liquid phase? Perhaps letting it boil off a solid, porous substrate such, ideally, as that from an empty acetylene bottle since acetylene at least, doesn't particularly like to be stored in the liquid phase, although if not under pressure, would that not largely mitigate any explosion risk? if in an open system that is.

(if nothing else, at least some of those absorbents use DMF as a solvent, some use acetone, and some DMF which wouldn't exactly be a crappy booby prize for effort expended)

[Edited on 1-6-2017 by tsathoggua1]

[Edited on 1-6-2017 by tsathoggua1]

Sure, but boiling points lie sufficiently apart (120 °C, 170 °C, 224 °C). Dichloropropane can be removed without vacuum, 1-chloro-3-iodopropane by aspirator vacuum, the diiodo compound remains and can be recycled or used for other reactions. I don't think this is a bad deal considering the easy preparation and workup.


EDIT: erroneous logic removed.

[Edited on 1-6-2017 by Alice]

EDIT2:

I was indeed using a model not suitable here which gave me 75% yield.

After having removed some errors, here is my revised numerical result for 1 eq. dichloropropane and 0.9 eq NaI. In the first place I tried out 1 eq. NaI, but it turned out this does no favor compared to 0.9 eq. and leads to a product ratio of 25% : 50% : 25% instead of 30% : 50% : 20% (rounded). The overall iodide efficiency therefor is 56%. Trying 0.8 eq NaI I obtained the following ratio: 36% : 48% : 16% giving a NaI efficiency of 60%. A is the dichloro, B NaI, C chloroiodo, and D is the diiodo compound. I hope this is free of silly errors now.



[Edited on 1-6-2017 by Alice]

[Edited on 2-6-2017 by Alice]

On the subject of heterocycles, I thought of a way to use 2-aminothiazole in order to avoid using other sulfur compounds. Unfortunately, I'm not sure how to synthesize 2-aminothiazole, although I don't think it's too hard. For the direct synthesis you can make a bromoacetaldehyde synthon via the reaction of a vinyl ether with Br2 IIRC.

Anyway, step 1 is a Mannich reaction, step 2 is just the addition of p-chlorophenethyl iodide to the nitrogen.

Step 3 is ozonolysis: my guess was that alkylating the nitrogen makes thiazole lose its aromaticity, meaning the alkene can be oxidized. The resulting dicarboxylic acid should eliminate to the thiourea.