A modification of Beaker´s method for 2C-H

[Rhodium]

But it was still able to form a hydrochloride salt?

[Sunlight]

You made de hydrochloride right ? make a single mp to see what happens, may be you are using bad more sophisticated ananlytical procedures.

[Barium]

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 Rhodium´s 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]

Have you confirmed that the am formate produces 2CH ? Well, it  is perfect, the AcOEt rdxn works... and it's great.

[Barium]

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]

You have found a treasure. My sincere congratulation.

[foxy2]

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]

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]

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]

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.......

[Rhodium]

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]

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]

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. Let´s combine our efforts and we will have two simple routes to 2C-H from the nitrostyrene using no LAH.

[slothrop]

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. Let´s 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]

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]

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]

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]

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

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]

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 don´t want to pay the destruction fee (it´s quite expensive), hence I don´t use it.

MeOH is not the solvent to use for the doublebond reduction.

[Beaker]

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!