Novel high-yielding C=C reduction of nitrostyrenes

[Barium]

The reduction of the double bond in nitrostyrenes has been a great source of pain for many researchers. It has traditionally been reduced by various metal borohydrides in yields varying from bad to great. The high-yielding methods has relied on huge excess of reducing agent, and in some instances huge amounts of solvents. Thus making these methods somewhat unattractive despite the good yields. Phase transfer catalysis (PTC) can be used to transfer reagents (or substrates) from a phase where it is soluble to a phase where it is insoluble. Using PTC a reaction can take place in a solvent in which it normally couldn't.


General method for C=C reduction of nitrostyrenes

To 25 ml toluene in a 250 ml roundbottom flask equipped with a magnetic stirbar is added 500 mg Aliquat 336 [1] and 20,9 g (100 mmol) 2,4-dimethoxy-beta-nitrostyrene followed by a solution of 4,2 g (110 mmol) NaBH₄ in 15 ml water containing 25 mg NaOH [2]. The mixture is violently stirred [3] for 1,5 hours while the temperature is kept at 25°C. The nitrostyrene gradually dissolves and the color changes from a dark yellow to a pale yellow as the reaction pregress. The color change is complete after about one hour but the reaction is allowed to go to completion by stirring for another 30 minutes.
The stirring is stopped and the mixture is transferred to a separatory funnel when the phases has separated the lower aqueous phase is removed and the organic phase is washed once with water and once with 25 ml water containing 2 ml GAA. The toluene is stripped of in a rotovap leaving a clear yellow oil weighing 21 g. 500 mg PTC was added so the weight of 1-(2,4-dimethoxyphenyl)-2-nitroethane is 20,5 g (97%).


[1] 500 mg Aliquat 336 is 1,2 mmol. The amount of PTC can be 1-5 mol % with little change in reaction time.
[2] NaOH is added to minimise the decomposition of the borohydride which otherwise starts as soon as the borohydride is dissolved in water.
[3] The two pahse mixture must be violently stirred, preferably a emulsion should be formed, in order to bring the phases in intimate contact.

Other solvents beside toluene can also be used. DCM is commonly used together with Aliquat 336 but pratically any water-immiscible organic solvent with which the substrate, product or reagent does not react can be used. The presense of PTC in the product does not disturb most further reductions of the nitro group. The pure nitroalkane can be isolated by vacuum distillation.

The following nitrostyrenes has been reduced with this method.

Phenyl-2-nitroethene (94%)
1-(4-Methoxyphenyl)-2-nitroethene (95%)
1-(2,5-Dimethoxyphenyl)-2-nitroethene (97%)
1-(2,4,5-Trimethoxyphenyl)-2-nitroethene (98%)
Phenyl-2-nitropropene (98%)
1-(2-Methoxyphenyl)-2-nitropropene (97%)
1-(2,5-Dimethoxyphenyl)-2-nitropropene (98%)
1-(2,4,5-Trimethoxyphenyl)-2-nitropropene (98%)

[SpicyBrown]

Barium,

This is most excellent! Have you subjected any of the nitroethane products from this alkene reduction to CTH or other nitro reducing reactions?

And.. Where DO you find the time to get all of this experimental work done?  

-SpicyBrown

[Chimimanie]

This is absolutely GREAT!  

I like to not use big amount of solvents and this reduction use so little, plain ol' toluene is very cheap, this reduction is so great!

BTW, does 25 ml of toluene dissolve the nitrostyrene, or is it a suspension?

You always amaze me, barium

Chimimanie  

[Barium]

SB: Yes I have. The PTC is of no problem if the KCOOH/IPA/Pd-C system is used to reduce the nitro group.

C: It is a suspension at first then it becomes a solution as the reaction progress.

[Greensnake]

Great, Barium.

One question though:

>solution of 4,2 g (110 mmol) NaBH4 in 15 ml water containing 25 mg NaOH [2].

Is necessary amount of NaOH really 25 mg (less than 1 mmol) ?

[pHarmacist]

It's nice to log on hive and see this kind of work. Who else can do stuff like this other than Barium? Barium, do you have any refs on this? Nothing more to say - Barium all the way!

[Megatherium]

The toluene is stripped of in a rotovap leaving a clear yellow oil weighing 21 g. 500 mg PTC was added so the weight of 1-(2,4-dimethoxyphenyl)-2-nitroethene is 20,5 g (97%).

1-(2,4-dimethoxyphenyl)-2-nitroethane

[cattleprodder]

Would you at least mind giving us some trip reports, specifically with the 2,4-dimethoxyamphetamine.  Thanx.

[Barium]

Greensnake:
Check [2] for the explanation why such a small amount NaOH is added.

pH: I have never seen anything published reminding of this method for reducing nitrostyrenes. When I read up on PTC some time ago I remember seeing something about aqueous borohydride behaving very well under PTC conditions. Then it was just a matter of make a few trials and then optimizing the method.

Mega: Thank you. I missed that one completely  
   
cattle. Ever heard of PIHKAL? Read it. You'll be amazed of what you can find in there.

[moo]

So this is completely your own work? Impressive... It might not be a great effort to you, but it sure is great for the Hive. I hope that someday there will be a wave of educated bees who got their first spark here and decided pay their debts to the Hive in the form of research.

[GC_MS]

1. DCM indeed works as well as toluene does, but be sure to use external cooling! I tried the procedure small-scaled, and a water-filled beaker was sufficient. I also tried the reaction without external heating, and the DCM evaporated completely. Although I could predict this, it was an entertaining view to see a RB flask being filled with foam  
2. The PTC does not interfere with the Zn/HCOOH reduction system. Might be a cheaper alternative for Pd/C  

A write-up will follow next week. First, there is some bioassay-ing to do!

[GC_MS]

I have been trying this method alot on p-methoxyphenyl-2-nitropropene. I am trying to find a good and cheap method to reduce the aliphatic nitro to the amine. Anisaldehyde is inexpensive, so I can toy around without wasting much valuable precursor.
I have screened the 4-methoxyphenylnitropropane reaction mixture with GC/MS several times, and I always noted the presence of an impurity which I believed to be 4-methoxyphenyl-2-propanone. During the night, I quickly performed a performic anethole oxidation to synthesize the ketone and compare the retention time/mass spectrum. There was a 99% match...
Now, there is no need to panic, no need at all. The GC peak area of the ketone amounts only 0.3%, but can still be found and identified.
Question: how does the ketone end up here? Might be Nef-related, but I thought you needed an acidic reaction environment for that. Any ideas?

[Barium]

That's interesting, very interesting. For a nef reaction to occur the nitropropene has to be reduced to the nitropropane. So how is it reduced then? Can this side reaction occur due to some impurity in the nitroethane? Imagine is one could find the right conditions to make this ketone formation the main reaction.

Edit

What in God's name was I thinking of when I wrote the above? Nitrostyrene formation apparently. I'll go away and put on the silly hat for a while.    

Interesting to see the nef reaction occurring under the alkaline conditions here. I wonder if this simple manipulation would be fruitful to make the ketone?

First the nitroalkene is reduced as usual. When the reduction is complete the excess borohydride is destroyed with dilute acetic acid. Then slightly more than one molar equivalent NaOH is added to create the sodium salt of the nitropropane which will move to the water phase. The toluene layer is then discarged. The aqueous solution is then added slowly to 2-3 molar equivalents dilute sulfuric acid. Now the nef reaction should take place. If so, the ketone (which should be visible as a oil) is simply extracted and distilled. I've never thought of this before. This must be tried soon

[Rhodium]

Another Nef variation:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenylacetone.html#p2np

- works okay for P2P, but for substituted nitropropenes the oxidation goes too far, forming aldehydes and acids...

[Barium]

I tried the method I proposed above  

1-(2,4-Dimethoxyphenyl)-2-nitropropene, 6 g (27 mmol)
NaBH₄, 1,2 g (32 mmol)
Aliquat 336
NaOH
Water
Toluene
Sulfuric acid

To a solution of 1,2 g sodium borohydride in 20 ml water containing 20 mg NaOH, I added 20 ml toluene, 6 g  1-(2,4-dimethoxyphenyl)-2-nitropropene and 0,5 g Aliquat 336. The mixture was violently stirred for 20 minutes at 30°C. The color had then changed from the initial dark yellow to nearly colorless. Dilute acetic acid was then added until gas evolution ceased and the aqueous phase discarged.

To the toluene solution of 1-(2,4-dimethoxyphenyl)-2-nitropropane and aliquat 336 was then added 2,5 molar equivalents NaOH (67 mmol, 2,7 g) dissolved in 20 ml water, and the mixture was then stirred violently for 20 minutes while the temperature was kept at 60°C. The toluene solution was then separated from the aqueous solution now containing the sodium salt of 1-(2,4-dimethoxyphenyl)-2-nitropropane. This aqueous solution was then added dropwise to diluted sulfuric acid (130 mmol, 12,7g in 100 ml water) with good stirring while the temperature was kept at 60° by heating.

The acidic solution became cloudy immediately upon adding the alkaline solution and some oily drops became apparent. I also noticed the ketone smell. When all alkaline solution was added the solution resembled milk with a yellow oil floating on the surface. The heating and stirring was continued for 10 minutes. This caused the milkiness to dissapear and gave a clear solution with the ketone floating on the surface. The ketone was isolated by extraction with toluene (2x20 ml), the combined extracts was dried over MgSO₄ and the solvent removed by distillation under reduced pressure. This left 2,8 g 1-(2,4-dimethoxyphenyl)-2-propanone (14 mmol, 51%).


Higher yields can be achieved if more nitroalkane can be dragged out of the toluene solution, as I suspect there is still more left in there. But hey, it's a good start!!

[Aurelius]

Damn Barium, is there anything you haven't tried or experimented with? (excluding all sexual references )

[Rhodium]

AFAIK, he has experimented with everything in both areas... Right, Ba?  

[Barium]

Unfortunately I won't be able to do more than a fraction of all I would want to do. But I'll make damn sure I do what I can to be a major pain in the ass to the turds in the DEA. As for the sexual area: I'll do as much "research" as I can there too  

[Aurelius]

Now, is that something that you regularly do?  

got some people that'd like you.

[GC_MS]

WANTED: Hive chick for never-ending lovemaking (in a rather erotic/perv way of acting) under the influence of GC_MS's Laboratory Products...  

Barium: How about evaporating the toluene and taking up the residue in NaOH solution? Or am I missing something obvious   ?