Sciencemadness Discussion Board - 5-Bromoindole preparation

5-Bromoindole preparation

karlos³ - 15-3-2015 at 11:18

Hello!
I would like to prepare 5-Bromoindole, and the usual procedure from Indole ive found, in means of making the sodium 2-indoline sulfonate, and then protecting of the nitrogen with acetic anhydride isnt so nice, as huge amounts of Ac2O are needed, and its hard to get for hobbyists.
I would like to know if anyone can suggest another Protecting group, to deactivate the pyrrole ring, which is also removable with base.
I would further brominate the sodium 1-acetyl indoline-2-sulfonate with bromine, then cleave the protecting groups on 1- and 2- with alkali hydroxides, to get 5-bromoindole.
I have much Indole, so i would like to do this route very much if I just find another suitable protecting group for the N-atom.

Ive also looked into making this compound from 5-bromo-2-nitrobenzaldehyde, via henry reaction with nitromethane, then reduction of the nitrostyrene to an aldehyde and the aromatic nitro group to an amine, with Fe dust and Acetic Acid, which would also result in 5-bromoindole.
But here I cant think of any easy synthesis of the benzaldehyde derivative.

Can somebody help me please?
Both these routes are already close to the price of 5-bromoindole, from which I dont need much of, but i really would like to perform some experiments with it. Simply buying it isnt what i want, and yes, Ac2O is nothing I can get easily, but 5-bromoindole is.

My references are:
5-bromoindole synthesis, erowid
4-acetoxyindol synthesis, lambdasyn

zed - 19-3-2015 at 16:23

Might be able to form from 4-bromoaniline phenylhydrazone.

karlos³ - 19-3-2015 at 21:37

Thank you for replying!
I thought about the Fischer-Indole synthesis as well, hey, i´ve even printed it on a shirt

.
But its such a long troublesome way, compared to the Speeter-Anthony (which I also printed on a shirt).
I would like to prepare some Analogues of some marine Tryptamines.
Well, I think I am just buying the bromoindole then if no ones else has a good idea...
Its not that I want to produce huge amounts, im just curious. A few grams would suffice and its not that expensive.

The synthesis via 5-bromo-2-nitrobenzaldehyde looks appealing, but i neither cant find something, nor think of any feasible route to it.
Could somebody help on this part maybe?

Fischer-Indole synthesis:

Speeter-Anthony synthesis

[Edited on 20-3-2015 by karlos³]

Waffles SS - 20-3-2015 at 00:49

is 5-bromo-dmt your final product?

CuReUS - 20-3-2015 at 01:58

Quote: Originally posted by karlos³

The synthesis via 5-bromo-2-nitrobenzaldehyde looks appealing, but i neither cant find something, nor think of any feasible route to it.

a quick google search should give many results
you could try nitrating 3-bromobenzaldehyde using H₂SO₄/HNO₃ at room temp for 4 hours to get the 5-bromo-2-nitrobenzaldehyde
http://khimiya.org/pdfs/052-065%20Pages%20from%20Khimiya%200... see page 7
synthesis of 3-bromobenzaldehyde
https://bbzfrankie.wordpress.com/2013/09/10/how-to-prepare-3...
http://www.google.com/patents/US4945186

[Edited on 20-3-2015 by CuReUS]

karlos³ - 20-3-2015 at 04:58

Thank you CuReUS, stupid me forgot that theres a Orgsyn preparation for 3-halogenation of benzaldehydes out there, which was the main problem I couldnt solve in the preparation of the 5-bromo-2-nitrobenzaldehyde, or otherwise spoken I havent thought of the 3-position for the halogen is after nitration the 5- position correctly named.
3-Halogenation of Acetophenone/Benzaldehyde
I also stumbled over the Tyrian Purple Syntheses, but forgot that they also prepared a 5,5-dibromo-indigo derivative of Tyrian Purple (6,6-dibromo-indigo).
Thank you, that was helpful from you puzzling all the pieces together, I was so focused on other parts of the whole thing, I didnt thought of this.
You´ve helped very much!

@waffles SS: No, not the 5-Bromo-N,N-Dimethyltryptamine, I am interested in the longer N,N alkylchains, the Diethyl, Dipropyl, and Diisopropyl Derivatives.
They look appealing to me, as Dr. Shulgin never made any halogenated Tryptamine as far as I know, but so many halogenated Phenylethylamines.
Should be worth a shot, Speeter-Anthony Tryptamine Synthesis, then reduction of the Dialkylglyoxylamides with Vitride als LiAlH4 substitute, fast and feasible.
As I said, they look appealing and are easy to make.
Also, 5-Bromo-N,N-Dimethyltryptamine is an active one, but gets possibly destroyed by MAO, thats why I would like to make the longer Dialkylamines than Dimethyl.

Waffles SS - 20-3-2015 at 08:50

Try below:

1.jpg - 18kB

5-bromo indole from indole

1: sodium hydrogensulfite / ethanol; water / 20 h / 20 °C
2: 2.5 h / 70 - 90 °C
3: water; bromine / 2 h / 0 - 20 °C

Antifungal agents. Part 4: Synthesis and antifungal activities of novel indole[1,2-c]-1,2,4-benzotriazine derivatives against phytopathogenic fungi in vitro
http://www.sciencedirect.com/science/article/pii/S0223523410007622

5-bromo indole from 4-bromo phenyl hydrazine + pyruvic acid
(With phosphorus pentachloride; zinc(II) chloride )
(Fischer indole synthesis)

A new and efficient one-pot synthesis of indoles
http://www.sciencedirect.com/science/article/pii/S0040403907024550

3.jpg - 19kB

5-bromo indole from 2-nitro 5-bromo toluene

1: pyrrolidine / dimethylformamide / 110 °C
2: 47 percent / Zn / acetic acid / 2 h / 85 °C

Metal-halogen exchange of bromoindoles. A route to substituted indoles
http://pubs.acs.org/doi/abs/10.1021/jo00376a010

[Edited on 20-3-2015 by Waffles SS]

zed - 20-3-2015 at 13:49

Dunno. If you have Indole, and only wish to form 5-Bromo-Indole, Erowid seems to have a decent procedure.

My Ninth edition of the Merck Index, suggests that 4-Bromophenylhydrazine, prepared from 4-Bromo-aniline, is a useful intermediate for producing 5-Bromo-Indole Acetic acid, via the Fischer.

Big Pharm, may be using the Fischer, as a route to Sumatriptan. As I recall, a Diazonium Salt, is reacted with Dihydrofuran to yield a phenylhydrazone. Which is then cyclized to form a Tryptophol. At which point, most of the heavy lifting has already been accomplished. You have a ring substituted tryptamine skeleton, now manipulate as required.

http://en.wikipedia.org/wiki/Sumatriptan

Not the exact sequence I'm recollecting, but interesting.

[Edited on 20-3-2015 by zed]

CuReUS - 21-3-2015 at 01:10

Quote: Originally posted by karlos³

No, not the 5-Bromo-N,N-Dimethyltryptamine, I am interested in the longer N,N alkylchains, the Diethyl, Dipropyl, and Diisopropyl Derivatives.
They look appealing to me, as Dr. Shulgin never made any halogenated Tryptamine as far as I know

yes,after I my last post,I immediately searched for 5 bromo tryptamine in Tikhal,but couldn't find it,there was only 5-OH and 5-OMe.but do you think the long chain trips are any good.?
DMT is visual,DET is auditory and DPT is sensory,but others ?

Quote:

Should be worth a shot, Speeter-Anthony Tryptamine Synthesis, then reduction of the Dialkylglyoxylamides with Vitride als LiAlH4 substitute, fast and feasible.

could Zn/Hg or Al/Hg in conc HCl be used instead of LiAlH₄ ?also be careful,you don't want the pictet spengler to happen

also TCCA in presence of 50% aq H₂SO₄ as catalyst could chlorinate the ring.even NBS might work ?

Quote: Originally posted by zed

Big Pharm, may be using the Fischer, as a route to Sumatriptan. As I recall, a Diazonium Salt, is reacted with Dihydrofuran to yield a phenylhydrazone. Which is then cyclized to form a Tryptophol

tryptophol can be made by fermentation
http://www.sciencemadness.org/talk/viewthread.php?tid=39224#...

Chemosynthesis - 21-3-2015 at 03:54

Despite my disinterest in discussing the chemistry directly, I will throw out a quip about the thread evolution. I can't speak on the totality of your specific compounds of interest, but some 5-halogenated simple tryptamines, such as are being discussed (contrast with ergolines) have been done by others than Shulgin. As renouned as the man was, he did not work in a vacuum. See Benington, Kochanowska, Bower, Nichols, etc. Bit of a niche market, in an academic sense.

Quote: Originally posted by CuReUS

Tikhal,but couldn't find it,there was only 5-OH and 5-OMe.but do you think the long chain trips are any good.? DMT is visual,DET is auditory and DPT is sensory,but others ?

Good? There is no such thing in pharmacology. Please be specific with the efficacy you refer to. Do you mean to ask if they are psychoactive? Any more specificity than a "yes" or "no" to any degree of confidence (i.e. probably/unlikely) is guesswork, as serotonin has a plethora of discovered receptors of various types, and almost certainly more to be discovered, much less specifics of the neural pathways they are involved with. There is plenty of evidence out there that some psychoactive trypamine effects are pharmacodynamically modulated by more than one serotonin receptor, and some psychoactive effects have been correlated to these (loosely), and this is ignoring transporters and metabolic enzymes for simplicity (they have downstream pharmacodynamic effects). Trying to guess psychoactive effects without some serious SAR and experimental data (or just the right empirically derived receptor model) per various receptors, in any real detail, is extremely troublesome once modifications begin. It also doesn't take into account the complexities of potential toxicity, which may outweigh any desired efficacy.

Often in pharmacology, extension of the alkyl substituents causes decreased affinity and subsequent diminishment of efficacy. In the crudest of senses, this may be assumed the case for (possibly erroneously) through comparing methylbutyltryptamine doses with the dimethyl versions, as well as ethyl variants, taking into account differences in bioavailability per route of administration and normalizing appropriately. Consider also the alpha alkyls, for further elucidation of sterics of various receptors. Psychoactive distinctions get interesting as you're one step removed from the neuropharmacology, and have to get into surrogate measures on top of the usual animal models in many instances. Biol Psychiatry. 1983 Jul;18(7):829-36. might be a good example.

Scr0t - 21-3-2015 at 10:50

Quote: Originally posted by CuReUS

..DET is auditory...

DET is definitely visual and sensory, it's DiPT that primarily targets auditory perception.

Mesa - 21-3-2015 at 12:30

Quote: Originally posted by Chemosynthesis

Despite my disinterest in discussing the chemistry directly, I will throw out a quip about the thread evolution. I can't speak on the totality of your specific compounds of interest, but some 5-halogenated simple tryptamines, such as are being discussed (contrast with ergolines) have been done by others than Shulgin. As renouned as the man was, he did not work in a vacuum. See Benington, Kochanowska, Bower, Nichols, etc. Bit of a niche market, in an academic sense.

Quote: Originally posted by CuReUS

Tikhal,but couldn't find it,there was only 5-OH and 5-OMe.but do you think the long chain trips are any good.? DMT is visual,DET is auditory and DPT is sensory,but others ?

Holy shit, a thread 10 posts long with 2 isolated sentences on subjective bioactivity...

Hell, that kind of subjective language is quite common from biochemists/pharmacologists/medicinal chemists when they aren't talking in a formal setting. It makes it easier to give a subjective opinion of efficacy without having to list each metabolic step or inhibition/variation that could occur. The last part of the sentence is pretty definitive of "good" in context.

karlos³ - 21-3-2015 at 12:51

Quote: Originally posted by CuReUS

could Zn/Hg or Al/Hg in conc HCl be used instead of LiAlH₄ ?also be careful,you don't want the pictet spengler to happen

Well I havent heard of any way to reduce the Indolglyoxylamide with any other Reducing Agent, you can maybe reduce the ketone this way, but not the amide carboxylic group.
I think besides Vitride/Red-Al which I want to use, theres only LiAlH4, probably some Diborane reduction Agent, and something else, I suspect it was Zinc Borohydride which reduces amides to amines?
But i really prefer Red-Al, thats a handy reagent, much more harmless then LiAlH4 to work with, almost all the same applications that it can be used for, but much less pyrophoric and so soluble, no suspensions, i like it.

Quote:

also TCCA in presence of 50% aq H₂SO₄ as catalyst could chlorinate the ring.even NBS might work ?

Ive read a paper about using NBS on tryptophol and indole acetic acid, and they dont produce the 5-bromo derivative, i think it was the double bond on the pyrrole ring which directs them to position 3- or 2, cannot remember, but sadly nothing what i want.

But if NBS could be substitute for elemental bromine on Sodium Indoline-2-Sulfonate, directly, that would be a very comfy and harmless synthesis to do, very appealing.

@Waffles SS:
The first reaction directly from Indole you mentioned, using sodium hydrogensulfite, sounds similiar to the route i found on erowid, but without adding an acetyl-group to the nitrogen before bromination.
That sounds pretty interesting, thats what I was looking for, i am going to ask for the paper in the references thread to get a look at the conditions, but that sounds very compromising and short.
Maybe the sulfonate is just bulky enough to inactivate the whole pyrrole ring, and allows direct bromination of the aromatic ring on position 5-.
That would be very nice.
Thank you!

Chemosynthesis - 21-3-2015 at 14:42

Quote: Originally posted by Mesa

People in the field use all kinds of language informally, especially after 5:00pm, but that isn't relevant to clarifying intended efficacy or the forum's semi-professional demeanor. Anyone in drug discovery and development has a target receptor in mind for a project.

A drug's benefit derives directly from intended use, which is very subjective in a non-medicinal setting. Is longer half-life (functional or chemical) important? Some psychoactive drugs last too long for the general use, recreational or otherwise, despite a duration of time between maintenance doses generally being favorable in medicine for patient compliance. Some psychoactives are dysphoric in nature, or some exhibit partial agonism at some receptors (particularly the 5-fluoro tryptamine, if anyone looks into the authors I mentioned, who synthesize and characterize such compounds). Clearly this may be undesired, despite my finding it interesting, so clarification is paramount.

Giving a subjective opinion of efficacy without a target or empirical data, even a bioassay, is worthless in science, especially when efficacy is undefined. Ignoring binding promiscuity of the parent compound, no metabolites, is just having any expected psychoactive effect "good?" Is dosage and cardiac toxicity of the parent compound (ignoring metabolites) an overriding concern? Are you aiming to try and replicate a specific type of 'trip' (type of hallucinationatory, euphoric, entactogenic, etc.) by replicating a pharmacophore for a specific receptor? Do you want to try to bias the functional selectivity thereof to see how that alters an experience? Do you want to try and reduce MAO metabolism, because this is obviously important in determining psychoactivity?

Etaoin Shrdlu - 21-3-2015 at 14:43

Quote: Originally posted by Mesa

"DMT is visual,DET is auditory and DPT is sensory,but others ?" doesn't do anything to define what the hell "good" means in context.

[Edited on 3-21-2015 by Etaoin Shrdlu]

Chemosynthesis - 21-3-2015 at 14:46

Karlos, have you checked any primary literature from other authors? Clearly you have done your research, so I don't mean to imply you have done none at all, but I am curious what you have looked at other than lambdasyn, erowid, and TIHKaL. Some authors have made various derivatives, often starting from a sourced substituted indole (not of as much use to you), but this was not always commercially available according to one publication.

[Edited on 21-3-2015 by Chemosynthesis]

karlos³ - 21-3-2015 at 16:04

Well ive seen the report somebody sent to Halmilton Morris from Vice on 5-Bromo-DMT which personal description of the effects of smoked 5-bromo-dimethyltryptamine, not the perfectly serious source, but it got me interested in what the other 5-bromodialkyltryptamines might do in humans.
I also know about some 5- or 6- Fluorotryptamines, but a fluorine atom is so much different in course of biological action, its not bulky enough to have the activity im interested in.
I even read a paper about brominated Psilocin analogues, but as far as I remember it doesnt mentioned any other longer dialkylamine groups than dimethyl.

Im just curious, even if my compounds in mind show they are inactive in psychoactive means, it doesnt matter much.
I simply want to synthesise those marine alkaloid analogues as pet project.

Also, 5-Bromoindole is available commercially, and it is comparably cheap, but not compared to the price of indole.
around 30 euros isnt what I want to pay for 5 grams of the substituted Indole, if for the same price im able to get a hundred grams of normal Indole, so, for the matter of making three differenct compounds in amounts which serve well enough for human testing, compared to the unsubstited dialkyltryptamines.
I am in the know of the activity of DET, DPT and the weird acoustic DiPT, i would really like to make at least a few gramms of brominated indoledialkylglyoxylamide of every of these three dialkylamine derivates, to compare their effect to the standard unsubstituted dialkyltryptamine.

No other analogue than the diethyl- dipropyl- and diisopropylamine of these is planned.
Maybe later then a 5-Iodo analogue of the most promising of them, there are some marine alkaloids called plakohypaphorines, which are halogenated quarternary trimethyltryptophane salts.
Iodine might be able to produce some interessting biological activity

(Just think about, 5-Bromo-Diisopropyltryptamine might be able to let you hear the waves breaking... just some sort of a joke i tell when asked about the intention of this unusual project

)

[Edited on 22-3-2015 by karlos³]

Chemosynthesis - 21-3-2015 at 18:30

Quote: Originally posted by karlos³

I also know about some 5- or 6- Fluorotryptamines, but a fluorine atom is so much different in course of biological action, its not bulky enough to have the activity im interested in.

Florine does usually substitute better for hydrogen than other halogens, though it is very useful to demonstrate what kind of modifications shift serotonin subtype affinity profiles, and possibly for synthesis schemes. Look into an author by the name of Benington I mentioned above. I listed him in addition to Bower and Nichols for a reason. The latter assist with the 5-fluoro pharmacophore models in serotonin receptor subtypes, and sterics such as with chlorine. The former and his group synthesized the 5-chlorotryptamine, a bioisostere rather than classical/chemical one, back in 1960. His work should be interesting to you in particular due to the following:

Quote:

Ive also looked into making this compound from 5-bromo-2-nitrobenzaldehyde, via henry reaction with nitromethane, then reduction of the nitrostyrene to an aldehyde and the aromatic nitro group to an amine, with Fe dust and Acetic Acid, which would also result in 5-bromoindole

You will find his data on the analogous chloro derivative synthesis interesting, I am sure. His reductive cyclization was a little different, but the results (or lackthereof) are worth looking at.

karlos³ - 21-3-2015 at 19:10

Yeah Im looking into it right now... I guess their use of Pd/C was the cause for the dehalogenation during the cyclisation.
I dont think this will happen when using Fe in acetic acid, or better, hope it.
Especially the sentences

Quote:

When the reductive cyclization of XXVII (5-chloro-2-nitrophenylnitrostyrene) was attempted in accordance with the method described
by Huebner, indole was obtained instead of 5-
chloroindole. This result is not surprising in light
of the findings of Strel'tsova and Zelin~kii, who
have demonstrated that hydrogenolysis of the
halo group occurs simultanieously with reduction
of the nitro group when either 2- or 4-chloronitrobenzene
is treated with hydrogen in the presence of
a noble-metal catalyst (palladium or platinum).
Since 5-chloroindole became commercially available
during this study, this was used in the synthesis
of the tryptamine VIII.

sound very discouraging.

http://bitnest.ca/external.php?id=%257DbxUgZ%255BC%2540Z%2504uzx%250DTWYQ

My lack of Ac2O is disturbing, they use so much to for the acetylation of 2- Sodium Indoline Sulfonate, and i cant find another decent way to deactivate the pyrrole ring for aromatic bromination,

Fischer indole on 4-Bromophenylhydrazone with dihydrofuran sounds better, despite the extra work, because making a tryptamine from tryptophol is a very rewarding experience, when doing it via the tosylate ester.

[Edited on 22-3-2015 by karlos³]

Chemosynthesis - 21-3-2015 at 19:57

If it works, I would find that very interesting, despite my expressed disinterest before.

To add to the discouragement, just in case you're not aware (sorry to be pedantic if you are), Nichols used the Hemetsberger–Knittel indole synthesis with methyl azidoacetate for several fluoro derivatives, and I am assuming you would like to avoid this (I would). While impressive, I am not sure he would have gone through this if not necessary.

CuReUS - 22-3-2015 at 02:12

Quote: Originally posted by karlos³

Quote: Originally posted by CuReUS

could Zn/Hg or Al/Hg in conc HCl be used instead of LiAlH₄ ?

Well I havent heard of any way to reduce the Indolglyoxylamide with any other Reducing Agent, you can maybe reduce the ketone this way, but not the amide carboxylic group.

actually I read this in a text book where they reduced the amide with Zn/HCl to get mescaline.But surprisingly I couldn't find a reference anywhere.

Quote:

But if NBS could be substitute for elemental bromine on Sodium Indoline-2-Sulfonate, directly, that would be a very comfy and harmless synthesis to do, very appealing.

I think NBS can be substituted for elemental bromine in all reactions.The only difference between them is that for Br₂,you use a drip funnel,whereas NBS slowly releases Br₂ in the reaction medium itself.That's why many labs nowadays use TCCA or hypochlorite instead of Cl₂ gas for their chlorination reactions.

I had another reaction in mind.Suppose you started of with o-toulidine.reacting this with Br₂ in CS₂ or any other non polar solvent should give you the 5-bromo-toulidine easily,due to the activating nature of NH₂
then you could oxidise the NH₂ to NO₂ using H₂O₂ and do the resseirt indole synthesis
http://en.wikipedia.org/wiki/Reissert_indole_synthesis

[Edited on 22-3-2015 by CuReUS]

Chemosynthesis - 22-3-2015 at 08:03

Quote: Originally posted by CuReUS

actually I read this in a text book where they reduced the amide with Zn/HCl to get mescaline.But surprisingly I couldn't find a reference anywhere.

Even good texts have errors. I have caught problems in medicinal chemistry books that mischaracterized citations, generalizing inappropriately to substrates and complained to editors. No fix last I checked. You would think correcting a factual inaccuracy would be on the publisher's "to-do" list since a new edition with corrections reduces the appeal of the secondary sales textbook market, from which a publisher makes no income.

Quote:

I think NBS can be substituted for elemental bromine in all reactions.

Not all. It offers greater selectivity, similar to low concentrations of bromine, without this restriction on concentration being as important. You use it to avoid dihalogenation of an alkene in lieu of allylic bromination, for example.

Quote:

I had another reaction in mind.Suppose you started of with o-toulidine.reacting this with Br₂ in CS₂ or any other non polar solvent should give you the 5-bromo-toulidine easily,due to the activating nature of NH₂
then you could oxidise the NH₂ to NO₂ using H₂O₂ and do the resseirt indole synthesis
http://en.wikipedia.org/wiki/Reissert_indole_synthesis

Doubtful. Giving you the benefit of the doubt on cleanliness of a peroxide oxidation of the given substrate, this doesn't address the cyclization issue I brought up. Read the source material, not the Wikipedia summary!
Org. Synth. 1963, 43, 40
A
Karlos' interest in iron rather than zinc should allow gentler conditions, though I am a bit skeptical they will be gentle enough. Zinc is moving in the opposite direction of the electrochemical activity series. Fischer and indole bromination are still top contenders.

karlos³ - 22-3-2015 at 10:34

Quote:

Fischer and indole bromination are still top contenders.

I am currently mostly interested in the Fischer to form 5-Bromo-Tryptophol, because ive read somewhere in the old hive posts, that instead of dihydrofuran other compounds can be used in the condensation with the Phenylhydrazine, to form Tryptophol. 2,3-Dihydrofuran isnt that easily available to me, so what could do the trick instead here? Is there any reagent thats more common? I stumbled over some other synthons, like Dihydropyran, but there are others, right?

4-Bromophenylhydrazine preparation from aniline should be easy, and compared to synthesising an dialkylaminobutanal-dialkyl acetal also a satisfactory deed.

From Tryptophol on, i know the reactions first hand, and even if the aminolysis of the ester uses much dialkylamine and takes days, its a very nice and clean synthesis.
Nothing fast like Speeter Anthony, but nonetheless also a very convenient reaction.

And to say it at least once, im very excited about all of your ideas offered, I really appreciate that, thank you all for chiming in into the discussion!

zed - 22-3-2015 at 15:34

Well, no route is especially easy. I suggested the Fischer because it avoids harsh reduction conditions. Just off hand, I don't know how well 5-Bromoindoles hold up to hydride reductions, and someone has already cited an example of dehalogenation via Pt/H2.

The formation of trypamines via the Grignard reaction works quite well, and is fairly straightforward, but once again...I do not know if Bromine at the 5-position can stand up to the reaction conditions.

The synthesis via the use of Dialkylamino- butyraldehyde looks OK, but you usually have to make the aldehyde, which is no small task. Likewise, you might have to make your own 2,3-dihydrofuran.

karlos³ - 22-3-2015 at 22:23

LiAlH4 Reduction leaves the Bromine atom untouched, and i think Red-Al will too.

Ive worked with indole grignards, reacted them with acid chlorides, and I personally dont like those reactions (even if i like grignard reactions very much, not those involving indole).
Even if I had 5-Bromoindole on hand, i wouldnt use it to make tryptophol or an dialkyltryptamine via grignard, because all the synthons for those are very toxic, like ethylene oxide for tryptophol, or those nasty mustard gas precursors for dialkyltryptamines.

Chemosynthesis - 23-3-2015 at 00:44

Karlos is correct. Further in the example is a reduction of the chlorindole. It is the preceding annulation that is difficult, but once that is accomplished, there seems to be additional leeway. Gassman indole synthesis should have good examples of halogenated indoles surviving reductions.
There is a pretty simple possibility in the classics.

CuReUS - 23-3-2015 at 01:35

I thought NBS might work because of this reaction
https://www.erowid.org/archive/rhodium/chemistry/safrole.htm...
upon close examination of the amide reduction given in the textbook using Zn,I saw that above the arrow between the product(mescaline) and the reactant(the corresponding amide) its given -"Zn/HCl" but under the arrow there is [H]
before I thought that the [H] referred to the nascent hydrogen produced due to the metal/HCl reduction but now I think it means that H₂ gas must be pumped in

but yesterday I found a good reaction using Zn,methanol and POCl₃
http://link.springer.com/article/10.1007%2FBF01936778
instead of POCl₃, maybe oxalyl chloride could be used.

[Edited on 23-3-2015 by CuReUS]

Chemosynthesis - 23-3-2015 at 01:56

You have been close to something that would work, in kind of a roundabout way. I feel confident if you were looking through more primary literature, you would find a very reasonable solution. I have one sitting in front of me.

CuReUS - 23-3-2015 at 03:12

Quote: Originally posted by CuReUS

you could try nitrating 3-bromobenzaldehyde using H₂SO₄/HNO₃ at room temp for 4 hours to get the 5-bromo-2-nitrobenzaldehyde

it suddenly struck my mind that this reaction might be wrong.Shouldn't the meta directing property of CHO dominate over the o,p directing nature of Br ?

Quote: Originally posted by Chemosynthesis

Quote:

Doubtful. Giving you the benefit of the doubt on cleanliness of a peroxide oxidation of the given substrate,.

this might be my lucky day,just found another beauty

.Maybe DMDO could be used as well
so I guess my idea is back on the table

Attachment: A Mild Oxidation of Aromatic Amines with Oxone.pdf (114kB)
This file has been downloaded 518 times

[Edited on 23-3-2015 by CuReUS]

Chemosynthesis - 23-3-2015 at 04:14

You are going about things the wrong way.
For aromatic directors, the most activating group takes directional precedence.

karlos³ - 23-3-2015 at 10:00

I cant think of all the indole i have readily, and just seem unable to put an acetyl-group on the nitrogen!
Its just a so simple procedure, I dont have to form the indole first, and simply just making the 2-sodium indoline sulfonate, then the n-acetyl derivative of this, brominating and just base hydrolysis to get rid of all the unwanted groups!

What about a transesterification maybe? I find my lack of acetic anhydride so disturbing, it would be so simple with it, or another way to put an acetylgroup to deactivate the nitrogen on it...
That is very annoying, despite all your brilliant suggestions, i have indole, it bothers me just to put the bromine on the right position, to form the ring all the way myself.

If i could just heat the sodium indoline sulfonate with ethylacetate, to N-acetylate it...

Chemosynthesis - 23-3-2015 at 13:32

You don't need an anhydride for what you are trying to do. You don't necessarily need to work through an acetamide either.

zed - 23-3-2015 at 17:37

Nowadays, you would probably have to make those "Nasty" mustard gas precursors too.

And, even that, might present difficulties. Thionyl Chloride is no longer an easy buy. At least, it is hard to obtain for many of us. Some members have corporate or university ties, which allow them fairly easy access to such reagents. Others do not.

Recalling my ancient days at the U.... an odd purchase, even then, might elicit a call from a curious control agent.

If you are in the U.S., and you have an itch that you just have to scratch, maybe a "handlers license" will be required.

karlos³ - 23-3-2015 at 22:19

Good thing I live in good old europe, have SOCl2, and can have more whenever i want!
A problem is, i am a private person, so its somehow comical what chemicals I can order, and which ones are forbidden to sent by standard post, university and others can use conveyance ordering for chemicals which arent allowed to sent (like MeOH, Oxalylchloride, some Hydrides, etc), but thats very expensive for private persons.
I even had to pick my oxalylchloride up in person, because its one of these chemicals.
They even want to put benzoic acid and concentrated formic acid on the list of toxic substances, so those cannot be mail ordered soon anymore in my country.

@chemosynthesis, ive found a reference where they use 2,3-dihydroindoline to brominate at 5-, do you refer to that?
Or using AcCl for that? I have Propionylchloride on hand, I wanted to use it on other pet projects, but if it would work here too, and the propionylgroup can be as easily cleaved as an acetyl after bromination, well, then I will use this.
If I dont have to use Ac2O for acetylating, that would be great.
In what solvent would this reaction be done, pyridine i guess?
If not, can you please elaborate more about what you are meaning?

Unrelated, but this night ive dreamed about 5-bromo homotryptophol, it disturbed me so much, i mumbled about too much carbon in my native language when i was fully awake as i havent seen that homotryptophol is one carbon too long...

[Edited on 24-3-2015 by karlos³]

Chemosynthesis - 24-3-2015 at 18:23

There are some citations available which utilize the carboxylic acid, much less an acyl halide or anhydride. They don't all acylate the same atom, depending on conditions, which is why your current method requires sulfonation. I didn't check yields... but I did notice that not all acylations require a protecting group at a 2 or 3 position.

CuReUS - 25-3-2015 at 01:49

Quote: Originally posted by karlos³

I had a crazy idea,maybe instead of trying to protect the N atom,we could try a different approach by removing/protecting the pyrrole ring double bond.Then I think normal halogenation should give the 5-bromo product,after which the double bond can be formed again.
http://www.scripps.edu/baran/images/pdf/pdf41.pdf
if you desperately need to acylate,why not just use good old ketene(I know its toxic,but if you take the right precautions...).there are many threads on SM about making a simple ketene generator.

Quote: Originally posted by karlos³

@Waffles SS:
The first reaction directly from Indole you mentioned, using sodium hydrogensulfite, sounds similiar to the route i found on erowid, but without adding an acetyl-group to the nitrogen before bromination.
That sounds pretty interesting, thats what I was looking for, i am going to ask for the paper in the references thread to get a look at the conditions, but that sounds very compromising and short.
Maybe the sulfonate is just bulky enough to inactivate the whole pyrrole ring, and allows direct bromination of the aromatic ring on position 5-.

looks can be deceiving,dont weigh your ppt before it dries,read the article first

Quote:

, 5-bromoindole (1b) was prepared from
indole (1a) in the presence of ethanol and 27% aqueous sodium bisulﬁte, followed by reaction with acetic anhydride and bromine

[Edited on 25-3-2015 by CuReUS]

[Edited on 25-3-2015 by CuReUS]

CuReUS - 26-3-2015 at 05:24

sorry for my stupid post.I realised that later that sulphite was being used to remove the double bond

aside from making amides to protect amines,you could also make carbamates(and they can be removed much more easily compared to amides).see this for synthesis of some alkyl carbonates
http://en.wikipedia.org/wiki/Carbonate_ester#Experimental_ro...

karlos³ - 26-3-2015 at 11:04

Well, thank you all for your input. I think I am going to make a gram of 2-sodium indoline sulfonate, and they divide the yielded substance in two parts, and try to acetylate it using refluxing ethyl acetate and also refluxing in glacial acetic acid.
I guess TLC and melting point will show me what comes out then, if its of any use.
Or maybe I should divide the indoline sulfonate by three and do the third reaction with a mixture of dry AcOH in EtOAc?

Really, I have to thank you all very much for participating in this discussion, there were many good ideas and opinions thrown in.
So I will go the way mad scientist do... experiment is king, so I will report what results I got(or if I figure it out, why results lacked).

Chemosynthesis - 26-3-2015 at 15:10

I think you're missing a catalyst and possibly a different solvent for that second reaction, based on what I was looking at.

karlos³ - 26-3-2015 at 21:21

Ah, thank you, Zinc acetate should it be then, in the microwave

.

Attachment: acetylation of amines in acetic acid under MW radiation.pdf (111kB)
This file has been downloaded 671 times

karlos³ - 4-5-2015 at 05:02

I apologise for not doing any experiments for making 5-Bromoindole, because I was fucking lazy and simply bought a few grams for my experiments. Will do then Anthony-Speeter Tryptamine Synthesis then with it, using diethyl- and 2-butylamine if anyone is interested in this, I will post about this instead.

CuReUS - 7-5-2015 at 00:53

are you going to extract the diethylamine from DEET ?

karlos³ - 7-5-2015 at 09:16

No, why? Its very cheap. Also, I cant source DEET.

CuReUS - 23-5-2015 at 01:10

this paper looks very promising for carrying out the bromination using NaBr .Unfortunately I can't access it.could someone get it ?
http://www.ingentaconnect.com/content/stl/jcr/2006/00002006/...
karlos,could you explain why you need to protect the N before brominating ?
also,could you post a write-up about a Red-Al reduction please ?

karlos³ - 6-6-2015 at 04:58

So, I did the glyoxylamide Preparation.
Ive prepared the Gloxylamide of 5-Bromo-Diethyltryptamine, an analogue of the marine Alkaloid 5-Br-DMT.
Still need to reduce it, but here is an photo-essay on how it was done:
5-Bromoindole
http://www.xup.in/dl,14021715/br_indol.JPG/
Oxalylchloride:
http://www.xup.in/dl,13524228/cocl2.JPG/

2g 5-Bromoindole were dissolved in 40ml MTBE, and 2,2g of Oxalylchloride were added in three portions, over 10 minutes, to a good stirred erlenmeyer flask sitting in an ice/salt bath.
After the first portion of (COCl)2 was added:
http://www.xup.in/dl,12940741/saeurechlorid.JPG/
After the addition was complete, sitting in the ice/salt bath on the stirrer:
http://www.xup.in/dl,16219134/eisbad.JPG/

After 30 minutes, the solid, yellow acid chloride was filtered and washed with ice cold MTBE:
http://www.xup.in/dl,21160994/festes_saeurechlorid.JPG/

It was added to 8ml cooled Diethylamine in two portions, 5 minutes between the first and last addition, while the Et2NH was allowed to come to RT and after 30 minutes, the solution with the suspended yellow flakes became all white.
There were added about 20ml dH2O and enough 7% HCl solution to make the solution weakly acidic, and no Diethylamine smell could be observed.
The precipitating glyoxylamide after addition of water and HCl:
http://www.xup.in/dl,17998806/amid_nach_reaktion.JPG/

And the dried, in EtOH recrystallised, fine Needles of the 5-Bromoindol-3-yl-N,N-diethylglyoxylamide:
http://www.xup.in/dl,14596823/dasendprodukt.JPG/

The yield was lousy, only 840mg of amide from 2g 5-Bromoindole.
But at least, i did it successfully.

@Cureus:
There are a lot of described reductions with Red-Al, some are even in Tihkal, some are on Erowid, very easy to find!

lullu - 8-6-2015 at 03:57

Very interesting, thanks for sharing Karlos!

Chemosynthesis - 8-6-2015 at 21:43

Agreed. Now that you have graciously shared your work, I will point towards an area that would be applicable for a chloro derivative (likely bromo too) in NMDA antagonists.