Boron-bridged MDxx

[Limpet_Chicken]

How stable would be methylenedioxy-amphetamines wherein the MEO O-C-O bridge is replaced by R-B-R ?

 

[S.J.B.]

A bridge consisting of R-BH-R or R-BR-R would be very unstable to air and moisture. An O-BH-O bridge would be more stable but would still be a fairly-reactive reducing agent (see catecholborane for example), and I imagine that O-BR-O might end up being a nucleophilic alkylating agent. However, a boronic acid derivative (O-BOR-O) should be fairly stable.

 

[Limpet_Chicken]

My bad, I should have specified R=boron, I meant, with the O-X-O atom being boron in place of carbon.

IIRC ethylenedioxy(alkyl)amphetamine and larger ringed compounds are none of them potent, buggrit, better ask the question and end up finding out its not a good start point than never ask in the first place.

 

[S.J.B.]

IIRC ethylenedioxy(alkyl)amphetamine and larger ringed compounds are none of them potent...

I'm not familiar with the whole series, but the ethylenedioxy homologue of MDMA is listed in PIHKAL as having fairly weak effects at up to 250 mg.

 

[Limpet_Chicken]

Yeah, the impression I got from PIHKAL was that ring expansion of the methylenedioxy bridge was a non starter. Never tried making it myself, but it doesn't really look like there is an awful lot of tolerance for steric bulk with respects to the bridge. So figured looking for bioisosteres for various bits, might be more interesting.

 

[sekio]

Cachetolboranes ("borylenedioxybenzene" ?) are known things, AFAIK they are hydrolytically unstable though.

They tend to be either reducing/hydroborating agents (R on the boron atom = H) or protected analogs of borinic acids (R = alkyl or aryl).

 

[Limpet_Chicken]

I have heard of it, come to think of it. Although I've never personally worked with catecholborane. Something along the lines of 'stinks something awful, pyrophoric and toxic as hell?'

 

[vecktor]

I have heard of it, come to think of it. Although I've never personally worked with catecholborane. Something along the lines of 'stinks something awful, pyrophoric and toxic as hell?'

Catechol boranes, water reactive, not exceptionally toxic, flammable but not very. Pointless to pursue in anything pharmaceutical unless it is for treating non aqueous animals and ammonia based aliens.
Even the boronic acid complex of catechol is unpromising (the -O-B(OH)-O) ring because it one will readilly disociate into catechol or 2-hydroxyphenylboronic acid and also form strong bonds to amino and other residues.
Perhaps the silacyclic analog would be more viable with silicon as the bridge -O-Si( R1R2)-O- where R is hydrogen it would be an unfortunate reducing agent and hydrolytically unstable, where R1=R2= Me it would be stable but lipophillic as hell. it should be made simply because it could be called SillE, probably both in name and nature.

 

[Limpet_Chicken]

Haha good one Veck, with the silylated analog

As far as the boranes go, most I know mostly from reputation, although I do have plans once a couple of other things are tested, for seeing how the yields compare with reduction of say, P2P ketoxime via Boveault-Blanc and use of diborane:THF or borane:THF adduct to reduce the potassium or sodium nitronate salt of the 1-phenyl-2-(beta-nitro)propanes in THF, otherwise I've only encountered pentaborane, and that was most offputting. Not in sufficient quantities to start a fire spontaneously, but the ungodly STENCH, jesus. Its one of the nastier things I've ever had kick me in my nose's bollocks. Reminded me of what a fridge full of dairy produce would smell like if it 'turned' really badly, and then began puking all over itself and rolling it's own vomit like Theresa May at a politician's orgy for the desperate, blind and wanting to become depressed and ashamed enough to give them sufficient impetus for suicide. Sickly soured gone-off milk mixed with barf and a nasty sweetish undertone that just made it a whole lot worse. Of course, I didn't hang around, being able to detect boranes by their odours is definitely cause in my book for getting the hell out of the way and masking up (it wasn't intended to be where it was).

No toxicological harm done, but that smell, absolutely vile it was. I'd say worse than mercaptans and similar rotting sulfurous abortions by quite a lot, not up to the thiols legendary powers to send people running for the hills from so far away, but qualitatively, pentaborane is all kinds of sickening and gutwrenching nose-rape that just ought not to be. I'd not be too surprised if the mental associations people form with things that are carriers of sickness and disease, like rotting food, decaying corpses of critters, putrid milk thats gone chunky, shit, pus etc. had something to do with it. I've smelled 'strongly, obscenely foul' in various ways before and that was definitely one of the most visceral feeling kinds of disgust, more than just hating the stink of it, it seems to go straight for the gonads, if one's digestive system had nackers attached to it to go for. And with their being none, it still seems to find a way to trigger that instinctive 'REJECT IT!' kind of feeling, in a way that mercaptans, H2S and their 'friends' just haven't got. It kinda did for my insides, what a strong whiff of chlorine does for your actual nose, at the point of contact. You don't think too much about it, just recoil as if it smacked you one with a baseball bat and started approaching wielding a large syringe and a vial marked 'autism spectrum 'disorder' 'cure' with a sadistic, evil looking smile on it's face.

 

[clubcard]

1-(1,3-dihydro-2-benzofuran-5-yl)propan-2-amine - unlike 5/6-APB, what is the activity if the single O is the bridge?

 

[Limpet_Chicken]

I was going to ask you the same thing, actually. I've never come across that one before. I've often wondered why not.

 

[clubcard]

I suspect the minimum-energy conformation will result in the O not being planer with the aromatic. For 5HT2a affinity, things like Bromodragonfly show it's important to be planer. I don't know much about it but the aromatic benzofuran derivatives are more potent than the dihydro analogues. If you consider 5-MeO ethylamines, the N is planer but I've not seen an example with the O as part of the aromatic. I know the 6 position overlays the para of PEAs so I guess N,N-dimethyl-2-(5-methyl-6H-furo[3,2-e]indol-8-yl)ethanamine and related derivatives would answer the question one way or the other.

 

[Limpet_Chicken]

That would make sense. What about for monoamine release/reuptake inhibition where 5HT is concerned? and for 5HT2b affinity (which, seems from my reading to be fairly important in MDxx for the entactogenic effects, or at least, lack of such affinity as an agonist impairs activity of that kind, as I read things. Although of course too much 5HT2b activation and/or for too long, has the well known potential for cardiac issues.)

Planarity seems to be a whole lot less important for stimulant type monoamine release however. If you consider the activity of things like cyclohexylisopropylamine, that pretty much qualifies as nonplanarity, a cyclohexane ring, with its boat and chair configurations. Or on a much more potent note, the likes of fencamfamine and camfetamine, with that hugely bulky benzonorbornane system (I always did wonder why the 'in vogue' period for camfetamine seems to have come and gone quickly, because its probably no.2 in favourite stimulants I've ever tried, with 3-fluorophenmetrazine coming in first place., was really nice smooth stuff, camfetamine, that is. Never tried fencamfamine.)

 

[clubcard]

TBH (R)-7-methyl AMT is a great MDMA mimic as is a 2:1 mixture of p-Me phenmetrazine : m-Me phenmetrazine. Those methyls are also sacrificial moieties i.e. metabolism is 100% by oxidation. I've always used defensive design so KNOWING the metabolism is important. 2:1 p-Me aminorex : m-Me aminorex is subjectively identical (but it's twice as potent i.e. x2 the potency of MDMA). There are are actually a LOT of PEAs, Indoles and (semi)-rigid derivatives that are identical to MDMA.

Beware of 5HT2b affinity.

 

[Limpet_Chicken]

Don't you worry about that, the 5HT2b affinity issue, I mean. I'm well aware of it. But also, I seem to recall that it is important somehow in the effects of MDMA etc. and that a 5HT2b antagonist or genetic knockdown wouldn't get the same experience.

 

[S.J.B.]

It turns out that there is a derivative of epinephrine, epinephryl borate, which contains a boric acid moiety:

Epinephryl borate is an approved drug for glaucoma, being topically administered to the eyes. Epinephrine's catechol moiety is highly oxidatively unstable in the presence of basic amine and therefore it is generally administered as a hydrochloride or bitartrate salt. The low pH of these solutions, however, leads to irritation. The boric acid moiety stabilizes the catechol and allows the administration of the drug as a non-irritating basic (pH 7.4) solution, where the addition of sodium hydroxide forms a sodium borate salt and the amine is in its basic state.

I wonder if such a compound could be isolated as the sodium borate salt? One could have solid salts containing freebase amines in that case. Still, this only seems useful for making prodrugs of catechols (or, presumably, other 1,2-diols), which would not be useful if looking for an MDMA analogue.