Barium
(Stranger)
05-30-02 19:05
No 315979
      A modification of Beakerīs method for 2C-H
(Rated as: excellent)
 Bookmark   

Call me a sissycrazy but I like to avoid ethers anytime I can. And now Iīve found a way of avoiding THF in a otherwise good procedure.

2,5-Dimethoxynitrostyrene is reduced by sodium borohydride to 1-(2,5-dimethoxyphenyl)-2-nitroethane. A reduction which has given many people gray hair prematurely. In theory it is simple and straightforward, but in practice it can be a great way to make tar.mad

Beaker found a method(my guess is from synthetic communications, 886-887, 1985.) and modified it slightly.
The authors tried 1,4-dioxane, THF, various mixtures of MeOH, EtOH or i-PrOH and said ethers, as well as the not too good chloroform/IPA/sillica gel. Beaker settled for THF since it is more readily avalible than 1,4-dioxane which the authors choosed.

It seems like neither the Indian authors or Beaker tried ethylacetate. I did!!....laugh

In a two-neck 250ml rb flask with a egg shaped stirbar containing 40ml EtOAc and 10ml denaturated EtOH(1), 3.63g(95mmol)NaBH4 is added in one portion. The flask is immersed in a 10 deg C cooling bath. A 4-bulb Allihn condenser(2), with cold tap water running through it, is inserted in the central neck and a thermometer in the side neck. Let the temperature drop to 15 deg C and start add 5g(24mmol)2,5-dimethoxy-beta-nitrostyene in 0.5g portions to the borohydride suspension. Keep the temperature between 20 and 30 deg C during the addition, which takes some 15 minutes. When all nitrostyrene has been added allow the reaction mixture stir for another 20 minutes.
Add 50ml cold water to the reaction mixture and stir for a couple of minutes. Transfer the mixture to a 500ml separation funnel and remove the bottom aquoeous layer(3). Add another 50ml portion of cold water, shake, allow to separate and remove bottom layer. Add a third portion of 25ml cold water and dropwise 50% aq. acetic acid untill gas evolution ceases. One might need to shake it now and then to bring the aqueous layer in contact with some borohydride still remaining on the walls. When no more gas is evolved add 50ml brine, shake, let separate and remove the bottom layer. Now you will have a bright yellow solution of the phenylnitroalkane in some wet EtOAc, dry with some MgSO4 and strip off the solvent to give a yellow oil. Yield 4.94g(98%) 1-(2,5-dimethoxyphenyl)-2-nitroethane, purity 97%(HPLC).

(1) If possible choose ethanol not denaturated with ketones. However the small content of acetone, MEK or other ketones does not interfer with the reaction sine they are reduced before the nitrostyrene is  added. The ketone content in regular denaturated ethanol is normally between 4-5%. If the only option is a ketone denaturation, calculate how much borohydride will be consumed and make the necessary correction.

(2) The reason for using a condenser is to minimise the loss of solvent carried along by the evolved hydrogen.

(3) This solution contains quite a bit of unreacted borohydride. Donīt just throw it down the drain. Kill the borohydride with some aq. acid first.


This method has been used up to 0.2 mol scale without complications.
 
 
 
 
    Sunlight
(Pioneer Researcher)
05-30-02 19:17
No 315981
      Good !!!  Bookmark   

It sounds very well, not huge volumes, very good yields... and not THF , very good !!!
 
 
 
 
    Barium
(Stranger)
05-30-02 19:20
No 315982
      Well thank you sunlight.  Bookmark   

Well thank you sunlight. Iīm pretty happy with it myself..wink
 
 
 
 
    Antibody2
(Rehabilitated)
05-30-02 20:10
No 316003
      nice to have options  Bookmark   

nice going barium

as well as the not too good chloroform/IPA/sillica gel. not too good is right
 
 
 
 
    Sunlight
(Pioneer Researcher)
05-30-02 23:40
No 316059
      solid nitro  Bookmark   

So you just added the solid nitro to the NaBH4 suspension, is it ok ? Did you powdered it before ?
If it works as you say perhaps we have a good kitchen method for mescaline and nitropropene rdxn, fine.
 
 
 
 
    Azarius
(Newbee)
05-31-02 02:07
No 316117
      :)  Bookmark   

Thankyou for this valuable contribution. I have 2 Qs:

1. What made you choose EtOH over IPA?

2. Would adding a small amount of dessicant (MgSO4?) to the rxn mixture improve yields?

Azarius
 
 
 
 
    Barium
(Stranger)
05-31-02 13:49
No 316265
      Toluene can be used  Bookmark   

Sunlight: Yes it was added dry. No need to ground it up. EtOAc is a good solvent for nitrostyrenes.

Azarius: Borohydride reacts with the alcohol to form the corresponding alkyloxyborohydride, which is the actual reducing agent. Ethanol reacts and forms mono-, di- or tri-ethoxyborohydride more easily than IPA(steric hindrance or not acid enough?). MeOH reacts too good with borohydride to be useful here.

Nah, I donīt see any reason to use any drying agent during the reaction. The water present will just protonate the nitronate intermediate.
---------------------------------------------------------------------------
I tried the same reaction with toluene instead of EtOAc, and it seems to work just as fine. The only drawback is that more toluene than EtOAc is needed, about 50% more, because the nitronate intermediate REALLY comes out as it is formed.
 
 
 
 
    Barium
(Stranger)
05-31-02 15:26
No 316285
      Another reduction method  Bookmark   

To 4g(19mmol) 1-(2,5-dimethoxyphenyl)-2-nitroethane dissolved in a mixture of 20ml MeOH, 10ml water and 10ml glacial acetic acid, 8,03g(76mmol) sodium hypophosphite and 50mg 5%Pd/C wetted with MeOH, was added. This was heated in water bath at 50 deg C and stirred until gas evolution ceased(approx 1.5 hours).
The catalyst was removed by filtration through celite and the filtrate acidified to pH2 with dil. HCl. MeOH was removed in a rotovap and the residue was made alkaline(pH12)and extracted with toluene(2x25ml). The solvent was dried with MgSO4 and gassed with dry HCl.
Yield 3.1g 2C-H*HCl(75.1%)tongue
Purity will be checked and identity confirmed tomorrow.
 
 
 
 
    hest
(Hive Addict)
05-31-02 16:00
No 316290
      Good  Bookmark   

Damm good work Barium. I'm impressed.
 
 
 
 
    Lilienthal
(Moderator)
05-31-02 16:26
No 316297
      Coooooool!!!!  Bookmark   

Coooooool!!!! But do you have analytical data that shows that you don't have an intermediate (like the nitro-ethane, the hydroxylamine, or whatever)?
 
 
 
 
    Sunlight
(Pioneer Researcher)
05-31-02 20:57
No 316370
      Good good good  Bookmark   

Nice news. Confirm the purity, personally I'm sure it's 2CH.
 
 
 
 
    Azarius
(Newbee)
06-01-02 00:30
No 316432
      :D  Bookmark   

Most impressive indeed :) However, I was under the impression that nitroalkanes can bee easily reduced to the corresponding amines via CTH @rtp with just HCOONH4 and Pd/C, as in the ref. below. Could somebee pls tell me if this would be another viable redn. procedure for this nitroalkane?

S Ram & R E Ehrenkaufer. A General Procedure for Mild Rapid Reduction of Aliphatic and Aromatic Nitro Compounds Using Ammonium Formate as a Catalytic Hydrogen Transfer Agent. Tetrahedron Letters 25(32), 3415-3418 (1984).

To a stirred suspension of an appropriate nitro compound (5 mmol) and 10% Pd-C (0.2 - 0.3 g) in dry methanol (10 mL), anhydrous ammonium formate was added (23 mmol) in a single portion. The resulting reaction mixture (slightly exothermic and effervescent) was stirred at room temperature for 3-40 min under argon, the catalyst was removed by filtration through a celite pad and washed with dry methanol (10 mL). The filtrate was evaporated either under reduced or at normal pressure. The resulting residue was triturated with water (10 mL - 25 mL), product was extracted with an organic solvent (i.e. ether, DCM or chloroform) and dried over Na2SO4. The organic layer on evaporation gave the desired amino derivative. Some products were directly converted into the HCl-salt with ethereal-HCl without evaporation of ether layer.

Many thanks,
Azarius
 
 
 
 
    Barium
(Stranger)
06-01-02 13:04
No 316626
      Well..  Bookmark   

Hest: Thanks

Lilienthal: I started with the nitroethane obtained by the modified borohydride reduction.
Aliphatic hydroxylamines are quite tough to got unless you use borane as the reducing agent.
This is just a simple transfer hydrogenation with hypophosphite as the hydrogen donor so it should not be particulary different than a CTH with formate.

Sunlight: It will be confirmed ASAP.

Azarius: The authors use a HUGE amount of catalyst so Iīm not surprised they get the job done. Iīm more into using more practical amounts of those noble metal catalysts. It has been my experience that aromatic nitro compounds are almost too easy to reduce, but aliphatic nitros are a bit tougher since they have a lower affinity for the catalyst. I also want to explore other hydrogen donors than ammonium formate in CTH.
 
 
 
 
    foxy2
(Distinctive Doe)
06-01-02 19:26
No 316687
      yes but...  Bookmark   


I also want to explore other hydrogen donors than ammonium formate in CTH.




How about exploreing some unlisted hydrogen donors.
tongue


Nice piece of work smile
Keep em comin!
Foxy


Those who give up essential liberties for temporary safety deserve neither liberty nor safety
 
 
 
 
    PrimoPyro
(Hive Prodigy)
06-02-02 02:10
No 316776
      How 'bout hydrazinium borohydride?  Bookmark   

How 'bout hydrazinium borohydride? I bet that would be a good hydrogenator. tongue
 
 
 
 
    Rhodium
(Chief Bee)
06-05-02 01:17
No 317650
      Great work Barium!  Bookmark   

Great work Barium! I'll incorporate any future comments/modifications into the document below:

../rhodium/chemistry /nitrostyrene.nabh4.reduction.html
 
 
 
 
    Barium
(Stranger)
06-05-02 11:46
No 317790
      Another substrate
(Rated as: excellent)
 Bookmark   

The same procedure was used to make 1-(3,4,5-trimethoxyphenyl)-2-nitroethane from 3,4,5-trimethoxy-beta-nitrostyrene. The only difference was that I allowed the temperature to rise to 45 deg C when 2/3 of the nitrostyrene had been added. Otherwise the reaction would have taken a long time due to the poor solubility of the substrate in the solvent. Will try again with toluene as solvent. The following amounts was used;

23,9g (0,1 mol) 3,4,5-trimethoxy-beta-nitrostyrene
15,2g (0,4 mol) NaBH4
200ml EtOAc
40ml EtOH

Yield 23,5g (97,5%) phenylnitroalkane as a colorless solid.
Purity 98% by HPLC
 
 
 
 
    Sunlight
(Pioneer Researcher)
06-05-02 11:55
No 317794
      You got it !!!  Bookmark   

I hope I can have soon the time to follow your steps. This is a very noticeable discovering.
Acording woth some info KrZ gave time ago, the best solvent for styrenes is just AcOEt, probably it is the best choice.
 
 
 
 
    Barium
(Stranger)
06-05-02 16:12
No 317840
      Another one
(Rated as: excellent)
 Bookmark   

This time I tried to reduce 1-(2-fluorophenyl)-2-nitropropene (just happened to have some on the shelf) to the saturated phenylnitropropane.

4,15g NaBH4 stirred happily in 50ml EtOAc and 10ml EtOH at 15 deg C.
5g 1-(2-fluorophenyl)-2-nitropropene was added in small portions. Be careful here!!
The first 250mg or so caused a violent bubbling, much more than the earlier ones. The temp rose 8 deg from that small portion. Wierd! When 1/3 had been added the suspension turned to a thick white paste which had to be diluted with more EtOH. So another 10ml EtOH was added. Kept on adding happily, but kept a close eye on the temp. When 2/3 was added, another 10ml EtOH had to be added. Paste again!! The total amount of EtOH added was 30ml. This will cause a problem in the workup since it will carry the ester and some product over to the water phase. This time I destroyed the borohydride with dropwise addition of diluted acetic acid to the rxn vessel. When this was done, 100ml toluene was added together with 50ml brine. The solvent layer washed two times with water, once again with brine, dried and stripped of solvents in a rotovap.
Yield; 4,3g (84,9%) 1-(2-fluorphenyl)-2-nitropropane as a clear yellow oil.
Purity; 97% (HPLC)
 
 
 
 
    Barium
(Stranger)
06-05-02 16:22
No 317843
      Bad News!  Bookmark   

I got my reference sample of 2C-H today. When I compared the 2C-H I made with the reference sample they did NOT compare at all. I made something by the CTH but it was not 2C-H...
Rest assure that I will devote this entire weekend to crack this nut.
 
 
 
 
    Rhodium
(Chief Bee)
06-05-02 18:13
No 317866
      Intriguing.  Bookmark   

But it was still able to form a hydrochloride salt?
 
 
 
 
    Sunlight
(Pioneer Researcher)
06-05-02 23:29
No 317949
      mp  Bookmark   

You made de hydrochloride right ? make a single mp to see what happens, may be you are using bad more sophisticated ananlytical procedures.
 
 
 
 
    Barium
(Stranger)
06-06-02 09:46
No 318159
      Rhodium: Yes it formed a salt, or something, with ...  Bookmark   

Rhodium: Yes it formed a salt, or something, with HCl.

Sunlight: I will check the mp. I think I will send a sample of this unknown to a friend with a NMR, because I really really want to know what this mysterious compound is.

-----------------------
Before I left yesterday I started a CTH the way beaker described with 4g of 1-(2,5-dimethoxyphenyl)-2-nitroethane, 5 eq. ammonium formate and 200mg 5%Pd/C in 50ml MeOH.
Two hours ago I filtered off the catalyst and stripped off the solvent and perfomed a A/B workup.
This gave 3,4g (82,5%) 2C-H*HCl.

I also added 5g 1-(2,5-dimethoxyphenyl)-2-nitroethane dissolved in 20ml toluene dropwise to 4eq. (26ml) sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) during 10 min, and allowed this to stir overnight at room temp. After the usual workup (which also is described on Rhodiumīs excellent page) this gave 4,65g (90,4%) 2C-H*HCl

This proves that the phenylnitroalkane was indeed the real thing, and that something odd happened in the first CTH I reported. This odd thing does not happen when CTH is performed with ammounium formate as the hydrogen donor. But I am confident that there is a way to get the CTH with sodium hypophosphite to behave the way we want. I will also try this with sodium and potassium formate as hydrogen donors.
 
 
 
 
    Sunlight
(Pioneer Researcher)
06-06-02 14:16
No 318217
      Right  Bookmark   

Have you confirmed that the am formate produces 2CH ? Well, it  is perfect, the AcOEt rdxn works... and it's great.
 
 
 
 
    Barium
(Stranger)
06-06-02 17:46
No 318272
      1-(2,4,5-trimethoxyphenyl)-2-nitropropane  Bookmark   

25,3g (100mmol) 1-(2,4,5-trimethoxyphenyl)-2-nitropropene was added portionwise to a suspension of 11,4g (300mmol) NaBH4 in 150ml AcOEt and 43,2ml (1,2mol) EtOH @ 20-25 deg C. A ice-water bath needed to cool the reaction mixture. The addition took 25 minutes. It was the allowed to stir at room temp for an additional 20min. Excess borohydride was destroyed with diluted acetic acid. When gas evolution ceased 100ml toluene and 150ml brine was added. The organic phase was washed twice with water (2x100ml) and once again with 100ml brine.
The solvent was dried with MgSO4 and stripped off in a rotovap.

The residue solidified to a clear yellow cake. This cake was dissolved in 150ml MeOH which gave a bright yellow solution. To this solution 500ml ice-cold water was added. This gave in 5min a thick slurry of colorless fluffy crystals which were filtered off and dried.

Yield 23,7g (92,9%) 1-(2,4,5-trimethoxyphenyl)-2-nitropropane
 
 
 
 
    Sunlight
(Pioneer Researcher)
06-06-02 21:33
No 318321
      Wow  Bookmark   

You have found a treasure. My sincere congratulation.
 
 
 
 
    foxy2
(Distinctive Doe)
06-06-02 22:08
No 318335
      hmmm  Bookmark   

I would bet you demethylated the 2-CH when using hypophosphite, just a guess

Those who give up essential liberties for temporary safety deserve neither liberty nor safety
 
 
 
 
    otto
(Hive Bee)
06-06-02 22:37
No 318342
      1-(3,4,5-trimethoxyphenyl)-2-nitroethane again  Bookmark   

a mixture of 16 ml EtOAc, 4 ml of EtOH and 1.5 g of NaBH4 was set up in a 100 ml RBF, which was immersed into an icebath. under magnetic stirring 1.8 g of 3,4,5-TMNS where added in small portions over the course of 15 minutes. stirring was continued for further 30 minutes and then 20 ml water were added to destroy excess NaBH4.

so far the same procedure as in Bariums first post (No 315979). it goes on:


Add 50ml cold water to the reaction mixture and stir for a couple of minutes. Transfer
the mixture to a 500ml separation funnel and remove the bottom aquoeous layer(3). Add
another 50ml portion of cold water, shake, allow to separate and remove bottom layer.
Add a third portion of 25ml cold water and dropwise 50% aq. acetic acid untill gas
evolution ceases. One might need to shake it now and then to bring the aqueous layer in
contact with some borohydride still remaining on the walls. When no more gas is evolved
add 50ml brine, shake, let separate and remove the bottom layer. Now you will have a
bright yellow solution of the phenylnitroalkane in some wet EtOAc, dry with some MgSO4
and strip off the solvent to give a yellow oil. Yield 4.94g(98%)


otto followed Bariums procedure and ended up with only 0.3 g of a yellowish product. why the bad yield? where has it all gone?
otto then acidified the aqueous phases and extracted again - et voila - the yield was 1.5 g (83%) of a yellow oil which solidified and gave colorless needles from EtOH. so far so nice, but then GC showed that the product (before recryst.) contains some 20% (!) impurities.

so,

it is important that you acidify the aqueous phase prior to extraction. for the impurities otto has no clue.

just wanted to add this

otto
 
 
 
 
    Barium
(Stranger)
06-07-02 09:54
No 318506
      Hmm  Bookmark   

Otto: Interesting to see someone else try this method.

When you acidified the aqueous phase what was you final pH?
Which acid did you use?

When I tried some years ago to reduce nitrostyrenes in pure alcohols, I got terrible yield when I acidified the whole thing. The meaning of acidification, I thought then, was to destroy the excess borohydride. But since the nitrocompound forms a nitronate salt during the reduction (all aliphatic nitrocompound can form salts) and nitrocompounds are not affected by acidic enviroments, I thought -hell bring it down to pH 1-2, just to be sure. Bad idea!
I think there will be a Nef-reaction, giving some ketone or aldehyde and other crap. My guess is that the answer to the 20% crap/unknown lies here.

 
 
 
 
    Barium
(Stranger)
06-07-02 15:17
No 318550
      TMA-2  Bookmark   

20g (78mmol) 1-(2,4,5-trimethoxyphenyl)-2-nitropropane was dissolved in 100ml toluene and added dropwise to 98ml (350mmol, 4,5 eq.) Red-Al diluted with 100ml toluene during cooling in a icebath. The addition took some 25 minutes and the temp was not allowed to rise above 80 deg C. When addition was complete the reaction mixture was stirred for 1 hour @ 70 deg C.

Then a test was done to see if there was still excess hydride left. A glass rod was dipped into the toluene solution and then immersed in water to see if any gas evolution or fizzing occurred. Yes it did, so there was still hydride not consumed. The excess hydride was destroyed with AcOEt added dropwise until the exotherm ended[1]. Then 66,5ml 5%NaOH was added and everything was stirred until all solids went into solution. The contents of the flask was transferred to a sep funnel and the bottom aqueous layer removed. The organic phase washed with 2x100ml water and finally with 100ml brine. The solvent was then dried with MgSO4 and diluted with more toluene to a final volume of 500ml. HCl dissolved in IPA was then added dropwise untill pH 5 was reached and the huge crop of crystals was filtred off. The crystals were rinsed with acetone and dried.

Yield: 17,51g (67mmol, 86%) TMA-2*HCl as white crystals.

[1] This is preferred over water because it causes no violent gas evolution.


30mg was dissolved in water and consumed 1,5 hours ago.
This the best stuff ever. Pure BLISS!!!
I sincerly wish everybody to experience this.

Tripping away.......smile
 
 
 
 
    Rhodium
(Chief Bee)
06-08-02 22:02
No 318927
      Nitrostyrene reduction
(Rated as: excellent)
 Bookmark   

It seems like Isopropanol can be used in good yields together with silica gel to reduce nitrostyrenes, thebelow synthesis is taken from Chem Pharm Bull 34, 1628 (1986):

3,4,5-Trimethoxyphenyl-2-nitroethene

The following components were placed in a one-necked 1000ml conical flask equipped with a Dean-Stark water trap (capacity about 30ml): 3,4,5-trimethoxybenzaldehyde (98.1 g, 0.5 mol), dimethylammonium chloride (81.5 g. 1 mol), nitromethane (300ml), toluene (300ml) and anhydrous potassium fluoride (4.36 g, 75 mmol). This mixture was vigorously refluxed with stirring for 5 h. The reaction flask was cooled down, then fitted to a rotary evaporator to order to remove the volatiles by gradual heating under reduced pressure. To the tepid residue (~55°C), chloroform (125 ml) and 0.2 M HCl (400 ml) were added. The mixture was heated on the water bath until complete dissolution. Then the flask was stored overnight in a refrigerator (-5°C). A crystalline solid was filtered out by suction, carefully rinsed with water and thoroughly dried in a vacuum oven. The filtrate was poured into a separatory funnel, the layers were separated and the aqueous phase was extracted with chloroform (3x100 ml). The organic extracts were combined then evaporated to give a crude oily material, which was chromatographed over silica gel (400g, eluent dichloromethane-ethyl acetate, 95:5). After removal of the solvent, the resulting solid and the previously separated product were recrystallized together from isopropanol: yield 99.2g (83%); mp 125.5-126.5°C (allotropic change at 121-121.5°C).

3,4,5-Trimethoxyphenyl-2-nitroethane

The following components were placed in a 6000ml wide-mouthed reaction flask provided with an efficient mechanical stirrer: isopropanol (750 ml), chloroform (2500ml) and the above nitrostyrene (47.8 g, 0.2mol). When the crystals had dissolved completely, silica gel 200-400 mesh ASTM (400g) was poured into the flask whilst the mixture was continuously stirred vigorously. Sodium borohydride (33.25 g, 0.88 mol) was then added portionwise over a period of 15 min. The slurry was stirred for an additional 2 h, and acetic acid (~50 ml) was carefully added. The insoluble material was separated by suction and the filtrate was evaporated in vacuo (the recovered solvents were used to rinse the silica gel thoroughly). The resulting crude material was taken up with dichloromethane (500 ml) and water (300 ml). The organic layer was separated, and the aqueous phase was extracted with dichloromethane (3x100ml). The combined extracts were dried with magnesium sulfate, filtered, then evaporated to dryness. The residue was chromatographed on a silica gel column (400g, eluent dichloromethane-ethyl acetate, 95:5) to give 3,4,5-Trimethoxyphenyl-2-nitroethane (46g), which was further purified by recrystallization (benzene-cyclohexane) to yield 44.6g (92.5%) as colorless crystals, mp 82-83°C.
 
 
 
 
    Barium
(Stranger)
06-10-02 18:15
No 319444
      Less borohydride...finally  Bookmark   

5g (23,9mmol) 1-(2,5-dimethoxyphenyl)-2-nitroethene was added in portions to 1,1g (28,7mmol, 1,2eq) NaBH4 in 50ml toluene and 10ml EtOH. The reaction was kept at 20 deg C by immersion in a cold water bath. When 2/3 had been added the temperature did not rise so fast after each addition so the remaining 1/3 of the nitrostyrene was added in one portion. After about one hour the solution had only a very pale yellow color. 20ml water was added, this caused a lot of bubbling and a white solid fell out of the solution. Diluted acetic acid was added dropwise until gas evolution ceased. Solid NaCl was added to the reaction flask and everything was strirred for 5min. The two phases was poured into a sep funnel, leaving some undissolved NaCl behind. The bottom aquoeous layer was removed and the toluene layer was washed with 2x 100ml water, dried with MgSO4 and the solvent removed in a rotovap leaving a pale yellow oil.

Yield 4,7g (92,8%) 1-(2,5-dimethoxyphenyl)-2-nitroethane    
 
 
 
 
    Barium
(Stranger)
06-11-02 14:14
No 319804
      The nitroalkane from the rxn above was used.
(Rated as: excellent)
 Bookmark   

The nitroalkane from the rxn above was used.

4,7 g (22mmol) 1-(2,5-dimethoxyphenyl)-2-nitroethane was dissolved in 50ml EtOH and this solution was poured into flask containing 200mg 5%Pd/C and a stirbar. 1,6g (42mmol) NaBH4 was dissolved in 5ml water and 10ml EtOH, this solution was added in portions of 1-2ml over 20min to the nitroalkane solution. The temp was maintained at 20 deg by immersion in a cold water bath. After the addition was complete the mixture was allowed to stir for 1 hour. Diluted HCl was added dropwise until gas evolution ceased and then further until pH 2 was reached. Two teaspoons of celite was added and stirred for one minute then everything was filtered at the water pump. The ethanol was removed in a rotovap and the aqueous solution was extracted with DCM (2x25ml) then basified with 50% NaOH soln until pH 12 and extracted again with 2x25ml DCM. The alkaline DCM extractions was dried with MgSO4 and the solvent removed in a rotovap. The residue was a oil with a yellow color. This oil was dissolved in 50ml diethylether and dry HCl in IPA added until pH 4 was reached. The crystals was filtred off and dried until constant weight.

Yield 1,4g (29%) 2C-H*HCl
Identity confirmed by HPLC

This simple reduction works but it has to be adjusted to achieve better yields. Letīs combine our efforts and we will have two simple routes to 2C-H from the nitrostyrene using no LAH.  
 
 
 
 
    slothrop
(Stranger)
06-11-02 15:05
No 319807
      Re: The nitroalkane from the rxn above was used.
(Rated as: excellent)
 Bookmark   



The nitroalkane from the rxn above was used.

4,7 g (22mmol) 1-(2,5-dimethoxyphenyl)-2-nitroethane was dissolved in 50ml EtOH and this solution was poured into flask containing 200mg 5%Pd/C and a stirbar. 1,6g (42mmol) NaBH4 was dissolved in 5ml water and 10ml EtOH, this solution was added in portions of 1-2ml over 20min to the nitroalkane solution. The temp was maintained at 20 deg by immersion in a cold water bath. After the addition was complete the mixture was allowed to stir for 1 hour. Diluted HCl was added dropwise until gas evolution ceased and then further until pH 2 was reached. Two teaspoons of celite was added and stirred for one minute then everything was filtered at the water pump. The ethanol was removed in a rotovap and the aqueous solution was extracted with DCM (2x25ml) then basified with 50% NaOH soln until pH 12 and extracted again with 2x25ml DCM. The alkaline DCM extractions was dried with MgSO4 and the solvent removed in a rotovap. The residue was a oil with a yellow color. This oil was dissolved in 50ml diethylether and dry HCl in IPA added until pH 4 was reached. The crystals was filtred off and dried until constant weight.

Yield 1,4g (29%) 2C-H*HCl
Identity confirmed by HPLC

This simple reduction works but it has to be adjusted to achieve better yields. Letīs combine our efforts and we will have two simple routes to 2C-H from the nitrostyrene using no LAH.  




You are the researcher of the month Barium!

This is from Synthesis pp713-714, 1987:

Reduction of Aliphatic and Aromatic Nitro Compounds with Sodium Borohydride in Tetrahydrofuran Using 10 % Palladium-on-Carbon as Catalyst

General Procedure

A 100 mL two-necked flask equipped with reflux condenser and stirred is charged with the nitro compound (10 mmol) in THF (40 mL). The solution is cooled by an ice bath and 10 % palladium on carbon (0.4 g) is added. NaBH4 (25 mmol) is then added in three portions over 10 min, the ice bath is removed, and stirring is continued at room temperature for 20-30 min. Excess NaBH4 is decomposed with 2normal hydrochloric acid (till pH = 6) and Et2O (70 mL) is added. The solid is filtered off and the filtrate is washed with H2O (2x15 mL) and dried (MgSO4). The solvent is evaporated to give the 95-98 % pure amine.

Yields for primary and secondary nitroalkanes are 70-80 %.

//Tyrone Slothrop

 
 
 
 
    slothrop
(Newbee)
06-21-02 19:37
No 323696
      3,4,5-Trimethoxy-nitroethane - troublemaker  Bookmark   


I found this passage written at the end of the Rainbow

9 g of 3,4,5-trimethoxy-nitrostyrene was reduced á la Barium's method in toluene. After destruction of the excess borohydride everything was vacuum filtered (this took about fucking 1.5 h) and washed with a little water and toluene. After drying there was about 7.5 g of a colorless solid.

The product was divided into two different reductions:

Reduction attempt 1:
CTH in MeOH with ammonium formate. During workup, when the Pd/C was filtered the filter paper was clogged with unreacted nitroethane. Insignificant yield of the phenethylamine. Maybe longer reaction time would have got the job done, but after 6 h of relfux there were almost no CO2 evolution.

Reduction attempt 2:
NaBH4, Pd/C in THF as listed above. Let stirr for 4 h after final addition of NaBH4. The story repeats: Clogged filter paper... Insignificant yield of the phenethylamine.

I hereby conclude that 3,4,5-trimethoxy-phenyl-nitroethane is the shittiest compound I've dealt with. It was really hard to clean the glassware from it. Didn't dissolve in acetone, so strong NaOH solution was used.


//Tyrone Slothrop


 
 
 
 
    Barium
(Hive Bee)
06-27-02 11:42
No 326004
      Better yields  Bookmark   

10g (47,4mmol) 1-(2,5-dimethoxyphenyl)-2-nitroethane was dissolved in 50ml EtOH containing 300mg 5% Pd/C in a 250ml rb flask. 14g (166mmol) potassium formate was dissolved in 9ml water (500mmol, roughly 3 eq) and this solution was added to the alcohol solution in one portion. The mixture was heated to 70-75deg C for 5 hours with good stirring.
During this time the mixture became thicker and thicker due to the precipitation of KHCO3. After three hours the mixture was too thick to be properly stirred so another 50ml EtOH was added. When 5 hours had passed the the reaction mixture was cooled to roomtemp and acidified to pH2 with dilute HCL , celite added and the catalyst removed by filtration. 100ml water was added to the filtrate and then it was extracted with 2x100ml toluene. The aqueous phase was the basified to pH 12 with 50% aq. NaOH and extracted with 2x100ml toluene. The organic phase was dried with MgSO4 and removed in a rotovap leaving a yellow oil. This oil was dissolved in 100ml EtOAc and gassed with dry HCL.

Yield 6,6g  (30,3mmol, 64%) 2,5-dimethoxyphenylethylamine HCl, mp 139-140°C.

In the presence of a catalyst hydrogen is formed according to: HCO2K + H2O __> H2 + KHCO3

For further reading check US patent 4,792,625
 
 
 
 
    Lilienthal
(Moderator)
06-27-02 16:11
No 326050
      ethyl acetate and alanate  Bookmark   

Barium Post 318550 (Barium: "TMA-2", Novel Discourse): By using ethyl acetate to destroy excess alanate you are probably ethylating at least a part of your amine (actually this is a known route to produce methyl-ethyl-tryptamines). There are at least two independent papers out describing this effect.
 
 
 
 
    Barium
(Hive Bee)
06-27-02 16:17
No 326052
      Oh shit!!  Bookmark   

I did not think of that...Silly me!!mad

But was thuroghly enjoyable anyway. Did not differ in effect from TMA-2 made by the same route but quenching the excess Red-Al with water.
 
 
 
 
    Barium
(Hive Bee)
06-28-02 09:16
No 326403
      I have thought about it a lot actually.  Bookmark   

I have thought about it a lot actually. But I NEVER use mercury, not even those few milligrams needed for a 10g batch 2C-H. I donīt want to pay the destruction fee (itīs quite expensive), hence I donīt use it.

MeOH is not the solvent to use for the doublebond reduction.
 
 
 
 
    Beaker
(Stranger)
07-17-02 12:14
No 333555
      It warms my heart...  Bookmark   

It warms my heart to see this.

Much credit goes to Barium and sunlight for their work on this subject.

Anyways, I had a few comments and questions for Barium.

The thing that dissapointed me about the Indian reference was that the nitronate salt never precipitated from the rxn mixture as stated in the paper. Given the fact that you are using a lower volume of a less polar solvent mixture(and not having to use THF, which is a real plus), and that you say that the nitronate comes out of solution when using the toluene/EtOH system, I believe that your solvent conditions are probably much better than mine for this reduction. Also, you do not say whether the nitronate crashes out with EtOAc. Is this the case, or is it soluble? I would think it would be much better if you could keep the nitronate out of solution in order to optimize the procedure to use a smaller excess of borohydride.

One thing that confused me was that you stated that you performed the ammonium formate CTH reduction in 82.5% yield, and then later post about doing the reduction with potassium formate with a yield of 64% for a better yield. Could you please elaborate on your experiences with the CTH reductions? As for myself, the >90% yield I got the 2nd time I did that CTH reduction has sadly not been reproduced. More like 70-80%. But I have only done that reaction a few times, so I'm not really sure what yield can be expected.

Also, have you made any attempt to quantify the amount of dimer in the NaBH4 reduction? I imagine it would be quite small, but it would be interesting to see how much you are getting, particularly if you are trying to reduce the amount of borhydride. In my experience, the dimer was very distinctly identifiable in the 1H NMR of the product and could be quantified even at low concentrations by integrating the appropriate peaks.

Keep up the excellent work!
 
 
 
 
    Barium
(Hive Bee)
07-17-02 13:13
No 333560
      I am not worthy...  Bookmark   

The inventor himself. Great to see you here again!!

The nitronate comes out when toluene is used, this can happen when ethylacetate is used as well. In those cases I usually add a little more EtOH to bring it into solution again. If all of the nitronate is allowed to fall out the volumes of solvent needed becomes quite high. Otherwise stirring becomes very difficult. 1,4-Dioxane is a good cosolvent if one wants to isolate the nitronate. I originally used dioxane, but since this solvent is really nasty I quickly decided to find another solvent.

The better yield, stated for the potassium formate was when I compared the yield from the NaBH4/Pd-C reduction which only gave a 29% yield. Iīm very curious to see the results of CTH with 2,5%Rh/2,5%Pd/C and various hydrogen donors.

Sadly my access to NMR is no more frown. I have not looked at the dimer content yet. Iīll try when I have time and proper equipment.

What are you up to nowdays?

It was truly great to hear from you.
Pls keep in touch
 
 
 
 
    Sunlight
(Pioneer Researcher)
07-18-02 00:57
No 333822
      Glad to see you again  Bookmark   

Your 70-80 % matches with my 65 overall yield. I had bad luck with your procedure and this was the only run that finished without any accident, I had some hazards, one time the flask fall from my hands to the floor, and other time the refluxer was stoppered  with crystallized ammonium bicarbonate, so the methanol was boiling under pressure, when my friend removed the refluxer... well, I still have the roof stained, but no more serious consequences. This is a important question to considere in CTH with ammonium formate under reflux, it is formed ammonium carbonate in the refluxer and it must be watch over.
The reaction seems anyway a bit capricious, and yields seem to vary considerably, for example a friend has recently performed it and reported about a 40 % overall yield.
 
 
 
 
    Barium
(Hive Addict)
03-02-03 18:02
No 413083
      Improvement
(Rated as: excellent)
 Bookmark   

Itīs time to bring this old thread back to life again.

100 mmol (18,1 g) 1-(2-fluorophenyl)-2-nitropropene, or any other phenyl-2-nitropropene
100 mmol (3,8 g) Sodium borohydride
50 ml EtOAc
20 ml EtOH
About 5 ml Glacial acetic acid
100 ml Water
60 ml DCM

To a 500 ml rb-flask, placed in a cooling bath and equipped with a magnetic stirbar and a thermometer, the nitrostyrene was added in one portion followed by the EtOH and EtOAc. Sodium borohydride was now added in portions of 1 g every five minutes while keeping the temperature between 20-30°C. When all the borohydride was added the reaction mixture was allowed to stir for another 30 minutes.

Glacial acetic acid was now added in 0.5 ml portions while the temperature was kept at 20°C. Before the acetic acid addition the color of the reaction mixture had changed from the initial bright yellow to a very pale yellow. When approximately 4-5 ml acetic acid had been added the last remaining yellow coloration faded away leaving a very thick practically colorless suspension, at this point the temperature tended to rise a bit due to stirring problems.

100 ml ice-cold water was now added in one portion and mixture was stirred vigorously for a couple of minutes. The liquids were decanted from some insolubles remaining on the bottom and transferred to a rotovap. The EtOAc was removed by distillation at reduced pressure. The nitroalkane was extracted with 2x30 ml DCM, the combined extracts dried over MgSO4, filtered and the solvent evaporated leaving a slightly yellow, fruity smelling oil.

Yield 16,3 g  1-(2-fluorophenyl)-2-nitropropane (89%).

Freaky
 
 
 
 
    SpicyBrown
(Hive Bee)
03-02-03 21:12
No 413127
      Sounds nice.  Bookmark   

Barium, when Beaker originally proposed his method, he used 4 molar equivalents of NaBH4 to avoid the formation of a dimer by-product. Have you checked for such a by-product by TLC or other means? Or is the dimer by-product not an issue for some reason with nitropropenes as opposed to nitroethenes?

-SpicyBrown
 
 
 
 
    Rhodium
(Chief Bee)
03-02-03 22:11
No 413150
      Only the nitroethenes dimerize uncontrollably.  Bookmark   

Only the nitroethenes dimerize uncontrollably.
 
 
 
 
    SpicyBrown
(Hive Bee)
03-03-03 01:06
No 413191
      Nice.  Bookmark   


Only the nitroethenes dimerize uncontrollably.



Excellent, thank you!

-SpicyBrown