Sciencemadness Discussion Board

Synthesis of 2-Nitropropane-1-ol

EilOr - 23-12-2017 at 21:58

Hi there!
I wonder if this interesting reactant could be prepared for example from formaldehyde and nitroethane by Henry-reaction?
Do you have any literature about the synthesis of this compound?

I was originally interested in the synthesis of 2-Aminopropanol-1-ol, but the synthesis of the educt seems to be even more interesting

There are tons of literature and patents for this henry-reaction using aromatic aldehydes instead of formaldehyde to form pharmaceutical percursers but the physical properties of the substrates are very different, so I doubt the same conitions could be used if Henry-reactions work at all for H2CO and EtNO2.

Literature; Mundy, Bradford P., Michael G. Ellerd, and Frank G. Favaloro Jr. Name reactions and reagents in organic synthesis. John Wiley & Sons, 2005. S.300-301



[Edited on 24-12-2017 by EilOr]

EilOr - 25-12-2017 at 00:59

Found one myself

Patent: US3560575 A
Preparation of 2-nitro-1-propanol
https://docs.google.com/viewer?url=patentimages.storage.goog...

A suspension of 33 grams of calcium oxide in 800 ml.
of water was prepared. A mixture of 75 g. nitroethane,
75 ml. of 37% formaldehyde and 30 ml. of methanol was added to the suspension keeping the temperature at about
25° C. The reaction mixture was agitated for 15 minutes
and dropped into 100 ml. of water through which carbon
dioxide was sparged. The sparging was continued for 15
minutes and then air was passed through for 15 minutes.
The mixture was ?ltered and passed through an ion
excange column in the same manner as in Example 3.
The ?ltrate was concentrated at 15 mm. at a temperature
of 65° C., and 2-nitro-1~propanol was then distilled at
a pressure of 0.5-1 mm. over a temperature range of
74-84° for a yield of 58%. On a duplicate run 6 meq. of
sulfuric acid was added before distillation and the yield was 61%.

The resin seems to be for removal of Ca2+ cations, without it might more dangerous to destill I guess!?
Yield is sad, I think I won't try it, at least not this way


[Edited on 25-12-2017 by EilOr]

Assured Fish - 25-12-2017 at 15:13

Seems sensible as this same or similar reaction is used in the prep for 2 nitro ethanol and some notorious nitro alkenes.

This if im not mistaken is the the Henry Reaction.
https://en.wikipedia.org/wiki/Nitroaldol_reaction

The calcium oxide forms calcium hydroxide upon hydration with water and this acts as the necessary base to deprotonate the alpha carbon and allow it to be attacked by the formaldehyde.
The use of CO2 for protonation is odd to me but i guess that is to prevent the formation of calcium sulfate, although i don't see why this is desirable.
Why would you not be able to use NaOH as the base and HCl to protonate is beyond me.

Might i ask why you are preparing 2-nitro-propanol? as its a rather specific product and nitro ethane is considerably less accessible than most other nitro alkanes.

Bert - 25-12-2017 at 15:43

Quote:
Might i ask why you are preparing 2-nitro-propanol? as its a rather specific product and nitro ethane is considerably less accessible than most other nitro alkanes.


Because it is the same person who was asking about making methadone/analogues & precursors for same a couple of days ago?

[Edited on 25-12-2017 by Bert]

EilOr - 25-12-2017 at 21:15

Quote: Originally posted by Assured Fish  
Seems sensible as this same or similar reaction is used in the prep for 2 nitro ethanol and some notorious nitro alkenes.

This if im not mistaken is the the Henry Reaction.
https://en.wikipedia.org/wiki/Nitroaldol_reaction

The calcium oxide forms calcium hydroxide upon hydration with water and this acts as the necessary base to deprotonate the alpha carbon and allow it to be attacked by the formaldehyde.
The use of CO2 for protonation is odd to me but i guess that is to prevent the formation of calcium sulfate, although i don't see why this is desirable.
Why would you not be able to use NaOH as the base and HCl to protonate is beyond me.

Might i ask why you are preparing 2-nitro-propanol? as its a rather specific product and nitro ethane is considerably less accessible than most other nitro alkanes.

Hi
Do you have or know any experimental sources that nitroethanol could be made in a decent yield by Henry-reaction? I thought you would end up with mmostly products like di(hydroxymethyl)nitromethane or even tri(hydroxymethyl)nitromethane (which might be also interesting compounds though) due high reactivity of nitromethane.
Would be an interesting read.

I think gassing with CO2 is only to prcp. Ca2+ as carbonate which is easyer to filter out of solution. Oxalic acid might be maybe an alternative.

HCl and other strong acids like H2SO4 for protonatiion would lead to Nitropropene-side-products due E1-elemination. Short chained nitroalkenes are extremly reactive, volatile, and potent toxic lachrymators, they so should be all avoided if possible. So CO2 seems to be a very smart way to me, as it couldn't harm the sensitive product. Also SN1-side-reactions with HCl could lead to 2-nitro-1-chloropropane as another side product, lowering the yields and purity.

Nitroethane is easy to get for me - A friend has a very old 250mL glass bottle of nitroethane from Merck getting yellow-brownish with a little precipitate already forming, I guess it's more than >40yrs old, collecting dust, so access would be no problem to me at all. I would be scared of destilling that old stuff as I already saw a fume-off from nitroalkylnates damaged another colleagues polycarbonate-goggles(!) without hurting that lucky bastard, so I thought it would would be a great educt compound as it has to be disposed anyway, though with that rather low yield I could expect I think I won't try it and the EtNO2 will collect dust for another couple of years ;)
Quote:

Because it is the same person who was asking about making methadone/analogues & precursors for same a couple of days ago?

:mad::mad::mad::mad:
Are you talking about me? Could you please explain that?
I didn't ask a single question about any drug related percurser AFAIK, and I don't see how ANY of the chemicals I mentioned or talked about in this forum would be useful at all for the synthesis of methadone!? For me asking about 2-nitropropan-1-ol and AlH3/DABCO-adducts as potential new catalyst seems (use the search engine with my nickname!) to be VERY far fetched to insinuate that I'm interested in making it or any analogues. Or did I miss something, as I also don't see how nitropropanol could be used for the synthesis of methadone at all?

I want to make 2-amino-propan-1-ol, as I said in my first post
I'm currently interested in making any kind of short chained alkylamines and partially their metal complexes later on
It is absolutely not related with any drugs!


[Edited on 26-12-2017 by EilOr]

[Edited on 26-12-2017 by EilOr]

Assured Fish - 29-12-2017 at 20:48

Mr EilOr, im fairly confident you are not a drug cook, for one you show a decent understanding of the field, as evident for you showing a greater understanding for the reaction in question than myself.
Also your post history wouldn't seem to suggest anything of the likes either, Im not sure why Bert accused you like so beyond the obvious use of this reaction in the production of nitroalkenes, it would be a hard push to get to cathinones via this reaction.

The reason i questioned your target compound however is because it could be reduced to the amine and the subsequently halogenated to 2-amino-halopropane where it could be attacked by a grignard reagent or organozinc reagent under controlled conditions to form the obvious amphetamine.
I do not assume everyone who asks such questions to be a drug cook however i must question them just to be sure of their intent. This forum gets weird sometimes.

As for experimental sources:
http://www.orgsyn.org/demo.aspx?prep=CV5P0833
yield 46-49%
No better than your ref.

However, in the oh so ironic drug literature there are reports of 85% yields, however these were performed on arenes such as benzaldehyde.
They do however seem to emphasize keeping the reaction temp below 20*C while adding the base to the nitroalkane aldehyde mixture.
https://erowid.org/archive/rhodium/chemistry/nitrostyrene.vo...

If we were to take all these write ups at face value then i would assume reaction temperature to be the main factor affecting yield.
Hope this helps.

Chemi Pharma - 2-1-2018 at 04:20

@EilOr, follow this recipe. No calcium oxide, nor exchange columns. Simple stir formaldehyde, nitroethane and K2CO3.

You'll get 2 nitropropane, 1- ol, substituting 53 grs of benzaldehyde by 40,54 grs of formalin (37% formaldehyde).

Then reduce it with your favorite choice to 2 amino propane- 1 ol:

Step I: Preparation of phenylnitropropanol
Into a suitable beaker or flask, place 53 grams of benzaldehyde, followed by 37 grams of nitroethane. Immediately thereafter,
add in 30 milliliters of a 30% potassium carbonate solution, and rapidly stir the entire mixture at room temperature for 2 hours.
Note: A cold-water bath may or may not be needed to keep the reaction mixture at ambient temperature (room temperature).
Do not allow the reaction mixture to get above 25 Cel sius. After stirring for 2 hours, add to the reaction mixture 200 milliliters
of diethyl ether, and shortly thereafter, add in 90 milliliters of a 10% sodium bisulfite solution, and then moderately stir the
entire reaction mixture for 30 minutes. Afterwards, place the entire reaction mixture into a separatory funnel , and then remove
the upper ether layer (after removing the lower aqueous layer). Thereafter, wash this upper ether layer with three 75-milliliter
portions of cold water. Note: after each washing portion, use a separatory funnel to recover the ether layer, which will be the
upper layer each time. After the washing portion, add to the ether layer, 15 grams of anhydrous magnesium sulfate (to absorb
water), and then stir the entire mixture for 10 minutes . Then filter-off the magnesium sulfate. Then, place the filtered ether
mixture into a distillation apparatus, or rotary evaporator, and remove the ether. When no more ether passes over or is
collected, remove the remaining oily residue (after allowing it to cool to room temperature). This oily residue will consist of the desired phenylnitropropanol.

[Edited on 2-1-2018 by Chemi Pharma]

Boffis - 3-1-2018 at 11:50

Can you prepare 1-nitro-2-propanol by the same reaction using nitromethane and acetaldehyde? :)

Chemi Pharma - 3-1-2018 at 16:12

I think so @Boffis, cause Henry reaction runs smoothly between an aldehyde and a nitroalkane.

The nitro group will always be attached to the carbon that makes the bond. Then, if you use nitromethane instead of nitroethane, you will get always a terminal nitro group while the hidroxyl remains at the alpha position.

Cause this, reacting acetaldehyde and nitromethane will afford 1-nitro-2-propanol, like you said and reacting formaldehyde with nitroethane will give 2- nitro- 1 propanol, the isomer.

Must remeber that if we don't use a base, like alkali carbonate, but an amine or ammonium acetate as a catalyser, we won't get a nitro alcohol but a nitroalkene instead.

zed - 10-1-2018 at 17:07

Ummm. Might be a handy precursor to Alanol.

The alternative, reducing the ester of the aminoacid Alanine, might be less than easy.

Alanol amides, are capable or performing some interesting Pt/Pd catalysed alkylations.

Sadly, nitroethane is no longer a whimsical acquisition in my jurisdiction. Guys may be obliged to make their own.

[Edited on 11-1-2018 by zed]

[Edited on 11-1-2018 by zed]

Dope Amine - 11-1-2018 at 00:14

Hey, going back to the amine idea, I'd like to suggest the following:

acetone + morpholine + ammonium iodide + sodium percarbonate

This will make 1-morpholinylacetone as it only works with secondary amines to make tertiary amines (unless there's a t-butyl or something similarly bulky).

If one wanted to go for a more boring target molecule then they could use dimethylamine. Another drawback of making the dimethylamine intermediate though is that it leads to one useful intermediate and one useless intermediate whereas the morpholino lead to two: one for phenadoxone and one for dextromoramide.

Anyway, the ketone would of course be reduced to the alcohol (via CTH (Pd/C + potassium formate in wet methanol), or NaBH4, or SmI2) before being converted to the chloride (SOCl2).

There's an interesting article to check out on SmI2 reductions btw. If anyone would be so kind as to share this article, this is the link to it:
Reduction of Carbonyl Compounds by Lanthanide Metal/2-Propanol: In-situ Generation of Samarium Isopropyloxide for Stereoselective Meerwein−Ponndorf−Verley Reduction


Now before anyone replies that I switched the alcohol and amino group from what was originally requested, that's because 2-chloro-1-whateveraminopropane and 1-chloro-2-whateveraminopropane react exactly the same in the base catalyzed attack on diphenylacetonitrile. But, if this whole thread is for some other much more boring purpose <sigh> then one could use propionaldehyde to get the amine on the 2 position.

Besides ammonium iodide + sodium percarbonate, another way to stick a secondary amine next to a carbonyl group is with CuBr2 in DMSO with the re-oxidant coming from ambient O2. Both articles are attached... ;)

Attachment: Cathinones directly from Propiophenones via Iodination with NH4I & Na Percarbonate.pdf (464kB)
This file has been downloaded 817 times





[Edited on 11-1-2018 by Dope Amine]

[Edited on 11-1-2018 by Dope Amine]

Attachment: cathinones directly from propiophenones with CuBr2 & DMSO SUPPORTING INFO.pdf (1.9MB)
This file has been downloaded 462 times



[Edited on 11-1-2018 by Dope Amine]



[Edited on 11-1-2018 by Dope Amine]

Attachment: php7qd4F9 (661kB)
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Dope Amine - 11-1-2018 at 00:20

I couldn't get the file uploader to work for one of the files in the previous post so I'm trying again in a new post...


What the fuck...

Attachment: phpVzYxoY (661kB)
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[Edited on 11-1-2018 by Dope Amine]

Corrosive Joeseph - 11-1-2018 at 01:45

Quote: Originally posted by Dope Amine  

If anyone would be so kind as to share this article, this is the link to it:
Reduction of Carbonyl Compounds by Lanthanide Metal/2-Propanol: In-situ Generation of Samarium Isopropyloxide for Stereoselective Meerwein−Ponndorf−Verley Reduction



/CJ



Attachment: Reduction of Carbonyl Compounds by Lanthanide Metal2-Propanol.pdf (105kB)
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Dope Amine - 12-1-2018 at 11:12

Thanks so much for that paper CJ!

I'm going to try posting the CuBr2 paper one last time. I changed the name of it because I'm wondering if the "%" that was in the name before was the reason it wasn't working. The CuBr2 is 20% molar and I often change document names to reflect such details. If this doesn't work then here's a LINK to a docslide of the paper. I already posted the supplemental info for it.

Attachment: cathinones directly from propiophenones with CuBr2 & DMSO.pdf (661kB)
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Dope Amine - 14-1-2018 at 13:38

Attached is proof that NH4I will work with aliphatic ketones as well as aromatic ketones...

Attachment: Iodination of ketones with NH4I and Oxone.pdf (3.4MB)
This file has been downloaded 810 times