Sciencemadness Discussion Board

2,5-dimethoxy-4-iodo-beta-nitrostyrene

turd - 6-4-2013 at 12:55

Attention: People who have mental issues with blatant cookery better stop reading. Save yourself the anger and myself the useless comments. Ghetto chefs read on. :)

Introduction

Professional chemists should be driven by rational reasoning, to improve the overall yield, reduce the total cost of a process or, in an academic setting, elucidate reaction mechanisms. Amateur chemists, on the other hand and as the name implies, work at least partially to satisfy their passion, an inherently irrational force.

Looking at the classical beta-phenethylamine multi-step synthesis from OTC materials under such non-rational criteria, the most significant step - the climax - is the reduction to the amine, usually either of nitro compounds or by reductive amination of ketones. The typical dissolving metal reactions used in amateur settings (Zn/HCl or Al/Hg) are relatively low yielding, give many side products, and are a nuisance in workup. Thus, after a successful reduction and workup the chemist is relieved and wants to savor the fruits of his hard labor. Unfortunately, in the classical synthesis routes of psychedelic phenethylamines of the 2C-X and DOX (X=Cl, Br, I) class, a further reaction is to be performed after the reduction, namely the halogenation. While chemically trivial, the side products can be difficult to remove and often a further distillation is called for. Thus, the idea was born to perform the halogenation at the benzaldehyde stage. While the overall costs are possibly higher, it may make the work of the chemist more joyous. All intermediate products can be reasonably purified by recrystallization.

Experimental

2,5-dimethoxybenzaldehyde was synthesized in very satisfying yields by Mg-mediated orthoformylation of para-methoxyphenol followed by methylation with DMS as documented elsewhere on this board. The aldehyde was thoroughly dried in vacuum.

2,5-dimethoxy-4-iodobenzaldehyde

Iodination of benzaldehydes is easily performed using the I2/AgNO3 system (Syn. Comm., 37, 3855-3860 (2007)). The atom economy seems bad, since half of the I2 is transformed into AgI, but the latter can be decomposed into Ag and I2. And let's face it: I2 is not that expensive.

Whereas I've seen this reaction mentioned as an oxidation, according to my (seriously lacking) understanding of synthetic chemistry the precipitation of AgI is the driving force:
Ag+ + I2 --> I+ + AgI
So the reaction seems to be more correctly described as a disproportionation. The nitrate salt is chosen for its high solubility and availability.

Anyway, based on the Syn. Comm. reference given above:

40 g of 2,5-dimethoxybenzaldehyde, 44 g AgNO3 and 63.5 g of I2 were suspended in 800 ml1 methanol and stirred for 18 h in a slightly stoppered round bottom flask at room temperature. There was a bright yellow precipitate of AgI and the solution was significantly less intensely iodine colored than at the beginning of the reaction. The AgI was filtered off, washed with MeOH and stored for reuse. The excess iodine was reduced with a thiosulfate solution. Just to be sure, a bit more than needed was added, which may have caused the troubles during recrystallization described below. The MeOH was removed in vacuo, and the residue suspended in 380 ml water, filtered and sucked dry.

Recrystallization from EtOH was a mess: There was a very fine grey solid which never dissolved and was assumed to be metallic Ag. Thus, the hot solution was filtered, whereby it (surprise, surprise) crashed out. After messing around with getting everything through the filter paper only negligible amounts of black powder were observed in the filter - thus the whole action was a waste of time. Amazingly, quite a lot of additional EtOH was needed to redissolve the crashed out product - distinctly more than can be explained by evaporation. After the second crystallization and drying, 52 g (74%) of very fluffy pale yellow needles were obtained, mp 140-141°C. Interestingly, for a few days the product reeked intensely of SO2 or NOx (rather the latter).

2,5-dimethoxy-4-iodo-beta-nitrostyrene

The well known ethylenediammonium diacetate catalyzed Henry condensation (https://www.erowid.org/archive/rhodium/chemistry/edda.html) seemed like a good candidate, given the succesful application to various similarly substituted benzaldehydes. The problem with the chosen aldehyde seems to be the low solubility as the following experiment demonstrates:

In a conical flask placed on a hot plate with magnetic stirrer 30 g 2,5-dimethoxy-4-iodobenzaldehyde and 1.8 g ethylenediammonium diacetate were suspended in 500 ml IPA. The contents were heated close to the boiling point of IPA (most of the benzaldehyde, but not all, disolves) and 15 ml MeNO2 were added. The heating of the hot plate was reduced and the reaction stirred for ~1.5 h at 65°C, giving a fine, intensely yellow precipitate. The hot plate was turned off and stirring continued for ~18 h. At that point TLC2 showed that significant amounts of unreacted benzaldehyde remained. Heat was increased and the reaction stirred for another 5 h at 65°C. which made practically all benzaldehyde disappear on TLC. The hot plate was turned off and the reaction stirred over night. No more benzaldehyde could then be detected by TLC. The reaction was cooled for 12 h at 4°C and the precipitate filtered off. Addition of 400 ml water to the yellow filtrate and cooling at 4°C produced minor amounts of slightly darker precipitate which was dumped3. Drying at 40°C for 24 h gave 32.4 g (94%) of a dense, intensely yellow4, microcrystalline powder of unknown purity5 with a mp of 175°C (dec.)5.

An experiment involving 3 h of reflux (~82°C) gave a dark brown solution and a brown, gritty product. Purification by recrystallization was difficult - all kinds of shades of yellow were obtained. Thus 65°C seems to be a sweet spot between speed of reaction and lack of side reactions.

Conclusion and outlook

These two steps seem to be unproblematic. The purity of the nitrostyrene and the perfect reaction conditions still have to be established, but the preliminary results suggest that excellent yields can be achieve on the chosen substrate.

The problem will be the reduction to the amine. The two commonly used ghetto procedures, namely Zn/H+ in methanol and Al/Hg in IPA are ruled out due to the low solubility of the nitrostyrene in the solvents, especially in MeOH. The options are usage of a co-solvent (THF?), prior reduction to the nitroethane, which hopefully has better solubility characteristics(?) or a completely different reduction system as for example NaBH4 followed by SmI2 in THF. The latter is unfortunately not as ghetto-friendly due to the need of dry solvents. Comments/ideas welcome.

Notes

1: The amount of solvent used in the literature seems to be optimized for dissolution of all the nitrate. Here, less solvent was used due to acute lack of an appropriately sized flask. In return the reaction time was increased.

2: DCM/cyclohexane 2:1, staining with KMnO4/Na2CO3. Benzaldehyde: Rf~0.41; Nitrostyrene: Rf~0.61. Staining with I2 as well as with KMnO4 does not seem to be ideal for this system - the former does not work at all, the latter works very well for the benzaldehyde but only so-so for the nitrostyrene. Actually, the nitrostyrene is observed more reliably by its yellow coloration than by the weak staining.

3: If larger amounts precipitate here, the reaction was not finished and the product still contains lots of benzaldehyde. The intense yellow color is treacherous - until the perfect reaction parameters are determined, monitoring by TLC is a must.

4: The color of the dried product is intensely yellow with a hint of orange. It could be described as one third of 2,5-dimethoxy- and two thirds of 3,4,5-trialkoxy-beta-nitrostyrene.

5: The purity of the obtained product is so far not well established. The melting point after the reaction is consistently 175-176°C (dec.), but a recrystallized product from an early run had a melting point of 194°C. It is unclear whether this was a fluke (confusion of samples?), the melting behavior is really that terrible or if there is a significant amount of impurities. Judging from experience with other amine catalyzed Henry condensations, the reaction looks very clean, but that doesn't mean a lot as we are all painfully aware. The recrystallization/melting point test will be repeated on fresh material.

Nicodem - 7-4-2013 at 02:26

Thanks for sharing. The quality of your contributions (should) set the norm for this forum.
Quote: Originally posted by turd  
Whereas I've seen this reaction mentioned as an oxidation, according to my (seriously lacking) understanding of synthetic chemistry the precipitation of AgI is the driving force:
Ag+ + I2 --> I+ + AgI
So the reaction seems to be more correctly described as a disproportionation. The nitrate salt is chosen for its high solubility and availability.

Indeed, most aromatic substrates (except for anilines, phenolates and similar) are inert for aromatic electrophilic substitution with iodine, but even electron poor substrates undergo this reaction with formal I+ species (I+ cannot exist as a ion in nucleophilic solvents).
Quote:
Interestingly, for a few days the product reeked intensely of SO2 or NOx (rather the latter).

According to your workup, the equivalent of the nitric acid that forms should have been mostly removed during the trituration in water, but leaching out might have been inefficient, particularly if the material was mostly amorphous (resinous or sticky). Same goes for the thiosulfate and its oxidation products. It is still strange that so much would have remained. Perhaps it would have been more efficient to just partially concentrate the filtrate and crash out with water. If performed carefully, slowly and with the right ratio of solvents, a crystallization of a pure enough product might be induced already at this step, making the recrystallization potentially unnecessary or at least better in regard to the inorganic impurities.
Quote:
2,5-dimethoxy-4-iodo-beta-nitrostyrene

The well known ethylenediammonium diacetate catalyzed Henry condensation (https://www.erowid.org/archive/rhodium/chemistry/edda.html) seemed like a good candidate, given the succesful application to various similarly substituted benzaldehydes.

The name of the described reaction is the Knoevenagel condensation. The Henry reaction is the name of the nitro-aldol reaction, a reaction that gives different products, the beta-nitroalcohols, and is not catalyzed by primary amines (tertiary amines or inorganic bases are generally used). The Rhodium archive is full of this misnaming errors apparently originating from misconceptions created at The Hive forum. Similarly, the rearrangement of styrene oxides or 1-arylglycols to aldehydes/ketones was obstinately named as the pinacol rearrangement (to which it admittedly somehow resembles until one considers that overall no C-C bond is being broken or created).
Quote:
The problem will be the reduction to the amine. The two commonly used ghetto procedures, namely Zn/H+ in methanol and Al/Hg in IPA are ruled out due to the low solubility of the nitrostyrene in the solvents, especially in MeOH.

The classical Zn/HCl is indeed susceptible to solubility issues, but the Al/Hg is less sensitive and THF can be used as the main solvent. It also runs well at higher temperatures, thus making the solubility less of a problem. However, I would be worried about deiodination when applying metal dissolving reductions or any other reductions based on SET mechanisms (SmI2, etc.). The most straightforward and expectedly certain method that comes to my mind is the reduction with NaBH4/BF3.THF. I guess you already have the reference, so I will not waste time searching for it.
Quote:
The options are usage of a co-solvent (THF?), prior reduction to the nitroethane, which hopefully has better solubility characteristics(?)

Yes, the arylnitroethane derivative would be expected to be much, much more soluble in alcohols or any other solvent.

turd - 7-4-2013 at 07:22

Thank you for the comments/corrections.

Point taken about the Henry reaction / Knoevenagel condensation. I used to designate the nitroaldol reaction as Henry reaction and the condensation as Henry condensation, but will use the correct names in the future.

You are right about the problem with deiodination: Even aromatic bromides are not useable with general SmI2 reactions: Tetrahedron Lett. 48, 5707-5710 (2007). (Note how the authors use the term Henry condensation erroneously too..). Fine - I'll save my small stash of Sm for another substrate.

You are probably aware that you are not making me happy with the suggestion of BF3-THF - what a nasty non-OTC reagent... If Al/Hg fails - and it looks like it will - I was rather thinking about catalytic (transfer) hydrogenation of the saturated nitroalkane. Though I realize that hydrogenations are much more tricky than they look like, especially since I have no experience with them. There are also various modified NaBH4 systems (in-situ NiB, etc.), but the little experience I have with them was not promising...

Edit: Ooops. Just found an article about the reduction of nitro compounds with Pd/C+NaBH4 - a Br on an aromatic ring is cleanly removed. Damn. :P

[Edited on 7-4-2013 by turd]

Nicodem - 7-4-2013 at 10:48

Quote: Originally posted by turd  
You are right about the problem with deiodination: Even aromatic bromides are not useable with general SmI2 reactions: Tetrahedron Lett. 48, 5707-5710 (2007). (Note how the authors use the term Henry condensation erroneously too..). Fine - I'll save my small stash of Sm for another substrate.

It is almost a sacrilege to use SmI2 on such a scale anyway.
And I know academic papers continuously misname reactions, perhaps just as often as amateurs. People just don't take the time to understand the mechanisms of the reactions they apply.
Quote:
You are probably aware that you are not making me happy with the suggestion of BF3-THF - what a nasty non-OTC reagent...

Yes, it is nasty and all, but it is the most sure path to take. BH3.THF is another alternative (it needs a bit of NaBH4 added in order for the reduction to proceed all the way to the amine: Tetrahedron 46, 7443-7457). Little has been done in the reduction of nitroolefins in regard to other in situ borane based reagents or other borohydride alternatives , but I would expect less nasty alternatives could work. Maybe with I2/NaBH4/THF, AlCl3/NaBH4/THF or even ZnCl2/NaBH4/THF or a myriad of similar alternatives, if you are willing to do research into reagent and conditions screening. Make sure to always have NaBH4 in excess over the acid or oxidant used to liberate BH3.THF. I would put my bet on I2 as an alternative to BF3.THF (besides, you say iodine is not that expensive).
Quote:
If Al/Hg fails - and it looks like it will

The member persona reported some troubles with a iodotrimethoxy-beta-nitrostyrene reduction that he atributed to deiodination. I don't remember if it was with Al/Hg as he preferred using Zn/HCl. I will try to find that post as soon as I remember which forum was that posted.
Quote:
I was rather thinking about catalytic (transfer) hydrogenation of the saturated nitroalkane.

Any hydrogenation over Pd, Ni or Pt based catalysts will cause deiodination for sure. It does not matter if it is CTH or external hydrogen.

S.C. Wack - 7-4-2013 at 12:20

One of the pinned chem threads at thenook has persona using zinc...a few months before his suicide afaik...

turd - 8-4-2013 at 06:00

Quote: Originally posted by Nicodem  
It is almost a sacrilege to use SmI2 on such a scale anyway.

True. Actually the Sm was acquired for selective reduction of 2-(2,5-dimethoxyphenyl)nitroethane to the corresponding hydroxylamine, but the project was put on indefinite hold for lack-of-time reasons. But apparently this can even be performed with neutral Al/Hg! In J. Chem. Soc. Perkin Tans. 1, 2000, 3487-3494 they make N-hydroxytryptamine from the nitroethane, though without workup. I still have some, albeit dirty, nitroethane - I should give this a shot.
Quote:
I would put my bet on I2 as an alternative to BF3.THF (besides, you say iodine is not that expensive).

Yes - that already sounds much nicer. :) Tetrahedron, 48, 4623-4628 claims reduction of, among others, amides (only aromatic) and nitriles, so nitro compounds maybe work too. I doubt that I will be able to pull it off, since I guess this would need reasonably dry conditions, but I have more than enough material to give it a try.

If I'm not mistaken, reduction of a nitroalkene needs 4 H2 equivalents, that means 2 I2 equivalents (or 1.5 for the nitroalkane), which is not so bad on a small scale.

In the end I see myself reducing the thing to the 4-H-phenethylamine and adding the halogen afterwards. That would be some sweet irony. ;)

[Edited on 8-4-2013 by turd]

[Edited on 8-4-2013 by turd]

Nicodem - 8-4-2013 at 07:23

Quote: Originally posted by turd  
If I'm not mistaken, reduction of a nitroalkene needs 4 H2 equivalents, that means 2 I2 equivalents (or 1.5 for the nitroalkane), which is not so bad on a small scale.

In the suggested method in the example using BF3.THF for the in situ BH3.THF generation they use a ratio of 1 : 4.75 : 6 for the nitrostyrene vs. NaBH4 vs. BF3.THF. This would translate to something like approximately 1 : 6.5 : 3.2 equivalents of your substrate vs. NaBH4 vs. I2. A slightly higher excess of NaBH4 should do no harm, but make sure there is no excess iodine.
Quote: Originally posted by S.C. Wack  
One of the pinned chem threads at thenook has persona using zinc...a few months before his suicide afaik...

No, I meant the report he sent at the Hyperlab about a year before his death, the post No. 523695 in the "Восстановление цинком\солянкой, прописи..." thread.

Edit: Corrected the BF3/BH3 copypasta error.
... For those who don't like to bother reading the referenced post: The deiodination deduced by persona's results resulted from his reduction of 2-iodo-3,4,5-trimethoxy-beta-nitrostyrene with the classical Zn/HCl. The claim is based on inconclusive evidence, but appears likely. (S.C. Wack, you are probably correct in that the posts are similar or identical, but I can't be bothered to register to that forum just to check that out. Persona was a member at many forums (including SM) where he posted about his experiments. He was a perspective chemist, unusually knowledgeable and intelligent for his age. It is so regrettable that he made such an irreversible decision.)

[Edited on 9/4/2013 by Nicodem]

S.C. Wack - 8-4-2013 at 12:49

Quote: Originally posted by Nicodem  

No, I meant the report he sent at the Hyperlab about a year before his death, the post No. 523695 in the "Восстановление цинком\солянкой, прописи..." thread.


Yes. The posting which I speak of and that which you do are as much the same as I said they were, per your description of course...in case someone cares and is a member there or was willing to sign up...no I'm not telling people which posts you've read where...

[Edited on 9-4-2013 by S.C. Wack]

turd - 21-4-2013 at 11:11

Sorry, no time for reduction experiments so far, just a small update:
Quote: Originally posted by turd  
5: The purity of the obtained product is so far not well established. The melting point after the reaction is consistently 175-176°C (dec.), but a recrystallized product from an early run had a melting point of 194°C. It is unclear whether this was a fluke (confusion of samples?), the melting behavior is really that terrible or if there is a significant amount of impurities.

Indeed, embarrassingly there must have been a mix-up. The 194°C melting sample was fine pale yellow needles. A new recrystallization of a small amount of the reaction product from EtOAc gave instead a quite dark, orange crystalline material (yellow plates under the microscope) with unchanged melting behavior. Moreover I was granted an audience with the oracle who confirmed that the non-recrystallized reaction product is indeed the expected compound and that it is single-phase.

Conclusion:
1) Forget the color - it is highly dependent on the crystal habit, varying from bright yellow microcrystalline to dark orange single crystals.
2) The reaction is very clean, high yielding and trivially worked up. Two thumbs up to the person who came up with the EDDA catalyzed nitromethane condensation.

Mildronate - 21-4-2013 at 11:27

How you will reduce it? Do you reduce it to amine or to ketone?

turd - 21-4-2013 at 12:23

Quote: Originally posted by Mildronate  
How you will reduce it?

Well, that is the crux of the matter. ;) I have no definite plans yet but will try to give one of the "modified NaBH4" methods a shot, though I seriously doubt that I will be able to make it work. Worst case scenario is Al/Hg down to 2C-H.
Quote:
Do you reduce it to amine or to ketone?

Ketone? This is a beta-nitrostyrene, therefore you could at most reduce it to the phenylacetaldehyde, which I will certainly try to avoid, since AFAIK they are even more reactive than the phenylacetones. And the Nef reaction has always stricken me as rude - you have the nitrogen in the magic position and then remove it!? If you want to make an N-alkyl phenetylamine maybe, but N-alkylation is a reliable inhibitor of psychedelic activity, so certainly not useful to me.

Mildronate - 21-4-2013 at 12:56

Sorry beta nitrostyrene

N-alkylation is a reliable inhibitor of psychedelic activity

To this compound only or?

[Edited on 21-4-2013 by Mildronate]

turd - 21-4-2013 at 23:56

Quote: Originally posted by Mildronate  
N-alkylation is a reliable inhibitor of psychedelic activity

To this compound only or?

AFAIK for phenethylamines and amphetamines in general. And only for simple N-alkyls, amazingly not for N-benzyl groups, which increase the potency of psychedelic phenethylamines (not amphetamines). And for those you would probably go via reductive alkylation of phenethylamine with benzaldehyde, not reductive amination of acetaldehyde with benzylamine. ;)

To me phenethylamine SAR makes no sense whatsoever, but I've never bothered to understand that receptor chemistry thing.

turd - 19-8-2013 at 13:54

Sorry, no significant things to report so far, due to lack of time.

Anyway, I decided to reduce it in two steps, since this gives more options and the first step - breaking of the conjugated pi-system by reduction of the double bond is well documented:
https://www.erowid.org/archive/rhodium/chemistry/2cb.beaker....
https://www.erowid.org/archive/rhodium/chemistry/nitrostyren...
https://www.erowid.org/archive/rhodium/chemistry/345-meo-ns....
And, indeed, finding good reaction conditions proved to be trouble-free.

2-(2,5-dimethoxy-4-iodophenyl)-1-nitroethane

A conical flask containing 60 ml THF[1] and 10 ml abs. EtOH was cooled in a cold water bath. Under stirring, 4 g of finely powdered NaBH4 was added and the suspension stirred for 5 min (slight foaming). 8 g of the beta-nitrostyrene was added in small aliquots over the course of 25 min, waiting after every addition for the yellow color to disappear[2]. The temperature of the reaction stayed cool to the touch for the whole addition. The cooling bath was removed and stirring continued for 50 min to obtain a dirty gray suspension with little foaming. 100 ml cold water was added and the reaction stirred for 5 min. The remaining hydride was destroyed by cautious dropwise addition of conc. HCl (strong foaming!)[3]. The solution then had pH~8-9 (universal indicator paper). The borax[4] was removed by vacuum filtration and the filter cake washed with a small amount of EtOAc. The combined phases were extracted with EtOAc (2x50 ml, 1x25 ml) and dried over Na2SO4. The solvent was removed under vacuum to obtain 7.8 g[5] of crude 2-(2,5-dimethoxy-4-iodophenyl)-1-nitroethane as a pale yellow microcrystalline powder, rather broad mp. ~80°C (nominal yield 96% :o). It contains at least two minor impurities[6] which can be removed as follows: The powder is stirred in ca. 20 times its weight[7] boiling MeOH, minor amounts of white insolubles are removed by filtration and the solution is cooled to -18°C for two days. Large pale yellow transparent crystals, m.p. sharp 86°C. The compound seems to be thermally quite stable, surviving a short heating to 150°C.

If all synthetic chemistry was that easy... :)

Notes:
[1] Attempts at using EtOAc or toluene as solvent failed miserably. The nitrostyrene does not dissolve well in cold EtOAc and heating lead to a darkening of the reaction product and formation of tar. Toluene gave small yields of an oil that crystallized in the freezer and had an extremely broad melting interval (~50-80°C).
[2] Consistently, foaming increased markedly after addition of ca. 50% of the styrene, possibly due to a slight temperature increase?
[3] Careful with local overheating - good stirring is a must or usage of dil. HCl.
[4] Virtually single phase.
[5] 0.5 g of which were removed from the distillation flask by dissolving in acetone followed by evaporation of the acetone. It sticks quite badly.
[6] One white, low solubility in MeOH (a borate?), one colored, good solubility in MeOH.
[7] Still experimenting with ideal conditions.

turd - 22-8-2013 at 00:42

Quote: Originally posted by turd  
It contains at least two minor impurities[6] which can be removed as follows: The powder is stirred in ca. 20 times its weight[7] boiling MeOH, minor amounts of white insolubles are removed by filtration and the solution is cooled to -18°C for two days.

Gosh, I'm losing my marbles. I give up on synthetic chemistry.

The crude nitroethane dissolves perfectly in acetone. I take a gram and boil it in 15 ml MeOH. Lots of white insolubles. I filter them of. They do not dissolve in acetone, nor in water. WTF? Dirt in the glass filter? Weird reaction? Madness setting in? :(

Nicodem - 26-8-2013 at 05:10

The insoluble stuff could be the oligomeric products arising from the conjugate addition of the nitronate salt to the starting nitroolefin. The nitronate of the dimer can react further to form more crap. This undesired pathway is the major problem of this reduction, especially for alpha-unsubstituted nitroolefins, and that is why so many unusual conditions have been tried (using just NaBH4 in methanol gives plenty of these dimers and oligomers).

Methyl.Magic - 15-9-2013 at 08:01

Hi,

I'm working on a totally new synthesis of phenethylamine by reduction of nitrostyrene with NaBH4 and sodium di-selenide as the catalyst. I will post the result as soon as I have.

stoichiometric_steve - 15-9-2013 at 08:33

Quote: Originally posted by Nicodem  
The nitronate of the dimer can react further to form more crap. This undesired pathway is the major problem of this reduction


…and this is why stirring the whole shebang with silica during NaBH4 reduction will reduce dimer formation by the mild protic acid that the silica is. demonstrated to greatly increase yields in the Fe/HCl reduction of indoles from nitroalkenes.

turd - 27-10-2013 at 10:25

Quote: Originally posted by Nicodem  
The insoluble stuff could be the oligomeric products arising from the conjugate addition of the nitronate salt to the starting nitroolefin.

I have no idea what it is - but it is completely colorless and looks microcrystalline under the microscope, so I don't think it's undefined oligomers. I'm not even 100% certain if this is already in the product or only is produced on heating with alcohol. A new experiment was inconclusive.

Since the two-step (nitroethene->nitroethane->amine) route seems not to be the way to proceed, I made a quick experiment:
2 g of the nitroethane containing this impurity was (not completely) dissolved in 30 ml acetonitrile with 3 ml water. To this was added 0.3 g finely powdered Ni(OAc)2.4H2O. The reaction was cooled in a water bath and under vigorous stirring 0.9 g NaBH4 was added in small portions over 20 min. The reaction was stirred over night (without removal of the water bath - doing so results in a noticeable temperature increase) and quenched with 50 ml H2O, resulting in a basic (to universal indicator paper) solution. A drop of conc. HCl did not result in a noticeable reaction, thus a small amount of 50% NaOH was added. The black solids were filtered of, the filter cake washed with toluene and the filtrate extracted twice with a small amount of toluene. The organic phase was washed with brine and dried over Na2SO4. The solution was significantly basic to wet universal indicator paper. Gassing with HCl and cooling to -18°C lead to oiling out of a red oil and deposition of white plates. Filtration, washing with acetone and drying gave 450 mg white crystalline material, mp 242°C (lit. 246-247°C).

Most will think that this is a colossal failure, but as a positive-thinker I say this is a successful proof of concept. :D

The Ni(OAc)2.4H2O was obtained by adding AcOH to a Ni carbonate/hydroxide suspension in hot water (takes a long time to fully dissolve!), evaporating most of the water, filtering and recrystallizing the pale green residue from water.

The procedure was adapted from a strange reference in Orient. J. Chem. which I don't have at hand, but should be easy to find.

Methyl.Magic: Yes, please!

turd - 11-1-2014 at 11:58

Ho-Hum.
There is at the moment not much interest in this project because the resulting phenethylamine was not received very enthusiastically. But since there is lots and lots of nitrostyrene left I thought I give the NaBH4/I2 reduction a try.

And: a preliminary experiment seems to indicate that there is a solubility problem! The BH3.THF solution was prepared by slow addition of THF/I2 at -5°C to a suspension of NaBH4 in THF. Then the nitrostyrene was added in one go to the completely colourless suspension. The reaction was slowly warmed to room temperature, whereby it turned from orange to pale yellow. On heating to reflux there was a fine voluminous white precipitate. Unfortunately more solvent could not be added since the chosen flask was too small and the thing was foaming like crazy. After reflux for 16h, hydrolysis (0.5 N HCl, 80°C, 2h) and cooling, some waxy yellow non-basics were filtered off. Basification, centrifugation, extraction with toluene, treatment with gaseous HCl led to minor amounts snow white microcrystalline material.

Will try again when I find time under more controlled conditions (bigger flask, dropwise addition of styrene at room temperature).

[Edited on 11-1-2014 by turd]

Nicodem - 18-1-2014 at 03:43

Quote: Originally posted by turd  
And: a preliminary experiment seems to indicate that there is a solubility problem! The BH3.THF solution was prepared by slow addition of THF/I2 at -5°C to a suspension of NaBH4 in THF.

What was the ratio of NaBH4 vs. I2? Did you assure an excess of NaBH4? Apparently, it has a catalytic effect on the reduction of the nitroolefins with BH3.THF (at least judging by DOI:10.1016/S0040-4020(01)89059-1 and other sources). It is also difficult to get the last reduction step from the N-hydroxy amine to the amine. Extensive reflux is probably a must.
Quote: Originally posted by Nicodem  
The deiodination deduced by persona's results resulted from his reduction of 2-iodo-3,4,5-trimethoxy-beta-nitrostyrene with the classical Zn/HCl. The claim is based on inconclusive evidence, but appears likely.

I found the experimental results reported by miamiechin at Hyperlab (post No. 562616) that prove that extensive deiodination occurs also with aluminium amalgam reduction. The reaction tested was the reductive amination of a ring iodinated dialkoxyphenetylamine with salicylaldehyde:
Quote:
It was found that the procedure fail with the corresponding iodinated PEA! HPLC-MS of the crude post-reduction filtrate indicated the presence of only 36% of NBOH-2-EtO-2CI along 64% NBOH-2-EtO-2CH when done in a similar way. The most impure bromo derivative was 97% pure contaminated by 3% dehalogenated PEA... Hence we can conclude it works well enough for bromo compounds but doesn't work with iodo compounds.

Not that this is surprising given the same occurs also with Zn/HCl.

turd - 18-1-2014 at 05:59

Quote: Originally posted by Nicodem  

What was the ratio of NaBH4 vs. I2? Did you assure an excess of NaBH4? Apparently, it has a catalytic effect on the reduction of the nitroolefins with BH3.THF (at least judging by DOI:10.1016/S0040-4020(01)89059-1 and other sources).

I was aiming for the ratio you posted above (1:6.5:3.2; 2 g nitrostyrene, 1.6 g NaBH4, 4.85 g I2) and added an additional spatula of NaBH4 for good measure. But I cannot exclude the possibility that the NaBH4 was already partially decomposed - it is quite old. At the beginning of the I2 addition decolorization was instant, versus the end it was significantly slower - maybe all NaBH4 was consumed and I made BI3? Next time I will try with a much larger excess of NaBH4.
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It is also difficult to get the last reduction step from the N-hydroxy amine to the amine. Extensive reflux is probably a must.

Yes, I've read the relevant papers, that's why I tried 16 h reflux. I know it's overly simplistic thinking, but if solubility really is the limiting step, then doubling the solvent should also double the yield, or at least improve it significantly, so that's what I will try.
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I found the experimental results reported by miamiechin at Hyperlab (post No. 562616) that prove that extensive deiodination occurs also with aluminium amalgam reduction. The reaction tested was the reductive amination of a ring iodinated dialkoxyphenetylamine with salicylaldehyde

Very interesting. Notably the fact that Br is compatible with Al/Hg - that gives me some naughty ideas. :) I will have to read that thread, at first it seems a bit strange to use Al/Hg in this case - why not form the imine on a Dean-Stark trap and then reduce it with NaBH4?

Edit: Is this thread in a non-open forum? When I enter the posting-id in the search-URL I get a "Not allowed on this forum" message...

[Edited on 18-1-2014 by turd]

Nicodem - 18-1-2014 at 09:37

Quote: Originally posted by turd  
Next time I will try with a much larger excess of NaBH4.

Do so, but don't get your hopes to high. The BH3.THF reduction of nitrostyrenes to amines is already sensitive as it is, let alone with an in situ reagent formation.
It is all a mater of reagent availability, but have you considered the use of in situ alane (you would need LiAlH4)? Also, DIBAL-H does a moderately good job on beta-unsubstituted beta-nitrostyrenes and should be compatible to iodoaromatics. Red-Al works excellently as well (see the Hyperlab examples), but I have doubts about it not causing deiodination.
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Very interesting. Notably the fact that Br is compatible with Al/Hg - that gives me some naughty ideas. :)

That fact has been known and employed for over ten years now.
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I will have to read that thread, at first it seems a bit strange to use Al/Hg in this case - why not form the imine on a Dean-Stark trap and then reduce it with NaBH4?

You could say that miamiechin is a fighter for amateur chemistry rights and does an excellent job in making things OTC-ish. He does this type of research with the military precision, taking good care to do all the necessary analytical evaluation in place of those who are more equipment deprived. This specific case was a present to those who do not have NaBH4. Otherwise, the same transformation is easily done by stirring the amine with the benzaldehyde in methanol for a couple of hours and then adding NaBH4 (no need to forcibly form the imine by Dean-Stark or otherwise - benzalimines easily form nearly quantitatively without troubles).
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Edit: Is this thread in a non-open forum? When I enter the posting-id in the search-URL I get a "Not allowed on this forum" message...

I'm afraid that - after the so called "Christmas reform" - the thread found its home in the Development crew section. Thanks to the Chinese drug labs and their greedy "research chemicals" dealers who continuously parasited the information of the site (and thanks to the politicians and their drug-law enforcers who happily allow this drug trade from China). Sadly, now the information must now be hidden behind an information exchange firewall - you can only access information after you give some.

turd - 18-1-2014 at 15:34

Quote: Originally posted by Nicodem  
Do so, but don't get your hopes to high. The BH3.THF reduction of nitrostyrenes to amines is already sensitive as it is, let alone with an in situ reagent formation.

Oh, that doesn't matter. In my few experiments I got more material than I want/need. This is just having fun with alternatives to the disagreeable Al/Hg and also some training - the next thing I want to try is the reduction of nitriles. And no, I don't have easy access to reductants of the aluminium hydride family.

Just for the records: I also tried twice an Al/Hg on the nitroethane in neutral THF at 0-5°C. There was obtained some yellow waxy non-basic (to wet universal indicator paper) material with a very broad mp, but above that of the nitroethane(!). Unfortunately the quality seemed to deteriorate on every recrystallization attempt and it was eventually dumped.
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That fact has been known and employed for over ten years now.

Sigh. I'm not following this very closely and have a memory like a sieve. :(

Methyl.Magic - 12-3-2014 at 15:10

Quote: Originally posted by Nicodem  
reagent formation.
It is all a mater of reagent availability, but have you considered the use of in situ alane (you would need LiAlH4)? Also, DIBAL-H does a moderately good job on beta-unsubstituted beta-nitrostyrenes and should be compatible to iodoaromatics. Red-Al works excellently as well (see the Hyperlab examples), but I have doubts about it not causing deiodination.


Hi, Red-Al causes dehalogenation for sure.

Could you please tell us the source of the hyperlab Vitride reduction because the rhodium archive reduction with vitride is claimed to give high yield but in fact did not work at all...

There are lots of methods which look promising and do not work AT ALL. Like the NaBH4/TMSCl of the nickel boride assisted reduction, so from now I am always wary of these too good to be true methods.

turd,

I am surprised the NaBH4 reduction method in THF gives you so much impurities (can you tell us the exact amount in percent of the product?) because adding the substrate TO the NaBH4 excess at LOW temperature usually forms low amount of polymers and gives very high yield (in AcOEt though). If the nitrostyrene is not soluble, I suggest you preparing a suspension of NaBH4 in AcOEt(containing a little THF as co solvent if necessairy), cooling to 0°C and adding sloowly a solution of the nitrostryene in THF (or any suitable solvent)containing 2-3 eq. of EtOH to gives the proton.

I think adding the solution dropwise limit the high concentration of the substrate that lead to partial polymerisation. Maybe triethoxyborohydride or triacetoxyborohydride instead of standard borohydride give a smoother reaction and no polymerised product.

Concerning the BH3 generation, I suggest you not destroying all the borohydride because this latter catalyst in the presence of borane the reduction of the double bond of the nitrostyrene. BH3 will reuduce the nitro group though the reaction usually stops at the hydroxylamine like for the reduction of oxime but you dont care because your stomach or your liver (dont remember) will cleave it to the good old free amine.

We are looking forward to the final high yielding protocol

Nicodem - 15-3-2014 at 03:23

Quote: Originally posted by Methyl.Magic  
Hi, Red-Al causes dehalogenation for sure.

Is that speculation or an experimental result? On what halogens?
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Could you please tell us the source of the hyperlab Vitride reduction because the rhodium archive reduction with vitride is claimed to give high yield but in fact did not work at all...

In the "The Khomeinines" thread (topic post #528139) you can find a couple of examples of arylnitropropenes reductions with Red-Al aka Vitride. Here is one example performed by his holiness the ayatollah Khomeini:
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3C-Kh3i: 5.42 g (18.4 mmol, MW 295) 3C-Kh3i NP is dissolved in 150 mL toluene (though 100 mL would have been sufficient) and is added drop-wise over a period of 30 min to an ice-cooled stirred mixture of 62 mL 70% vitride (~12 eq) and 50 mL toluene. The ice bath is maintained a further hour when addition is complete and the reaction is allowed to continue overnight. It is subsequently neutralized with 5% aq NaOH and the organic phase is isolated. The latter is washed with 2x 100 mL 5% aq NaOH and 2x 100 mL brine. The organic phase is extracted with 3x 100 mL 10% aq HCl and the combined extracts washed with 75 mL toluene and neutralized with 40% aq NaOH. The neutralized mixture is extracted with 3x 150 mL dichloromethane and the combined organic phases dried over sodium sulfate. After filtration of solids and evaporation of volatiles, 4.33 g of a slightly yellowish oil remains. This is taken up in 75 mL MeOH and neutralized by addition of 4 mL 5 N IPA/HCl. Evaporation of the alcohols gives a crude powder which is recrystallized from CH3CN/IPA, yielding 3.73 g (66.8%, MW 303.5) of a glistering powdery substance, mp 154-155°C.
MS: 267 ([M]+., 0.03%), 44 ([C2H4NH2]+, 100%), 224 ([M-C2H3NH2]+., 5.3%), 182 ([M-C2H3NH2-C3H6]+., 16.3%), 153 ([m/z 182-C2H5]+, 6.4%), 154 ([m/z 182-CO]+, 4.7%)

See also his report in the "3C-E (Vitride reduction)" thread (#521627).