The most interesting CTH reaction ever documented?

[Regis]

Acetylation of the alcohol group has been reported to work using sulfuric acid and acetic acid. This is old news.  Applying the technique listed in the patent--which is diluting the acetic acid mixture with hexane; perhaps Coleman's Camper fuel might work--might be to some advantage. 

But who cares?

What's more interesting is the following theoretical proposal:

1.) Apply the Friedel-Crafts acylation reaction to form the acetophenone of your choice.

2.) Brominate this using standard proceedures (1:1 aqueous methanol oxone/NaBr might work but the paper describing such a reaction seems to indicate that nuclear bromination might occur with 'electron-rich' aromatic systems).

3.) Substitute the bromine atom with hexamine (any side chain longer than that of acetophenones will not work); hydrolize with HCl to form the aminoketone-HCl.  This maybe can be done in situ after the completion of the above oxone/NaBr reaction. Reduction of any excess oxidant with either bisulfite, thiosulfate, or 2-propanol, plus the addition of sodium carbonate until the solution is lightly basic would be in order to prevent hydrolysis of the hexamine into formaldehyde and ammonium chloride.  This is of course assuming that hexamine is hydrolyzed by HCl only (and not by other acids such as potassium bisulfate). 

Anyway, the acylophenone-hexamine complex should precipitate as such complexes are reported to be insoluble in most solvents (don't know about water though). This would necessitate that the solution be filtered and the filtered complex hydrolyzed in ethanolic-HCl to allow easy separation of the desired aminoketone-HCl.  (I have a few references that detail this substitution reaction.)

4)  Reduction of the carbonyl group of the aminoketone-HCl using the present CTH reaction should provide the desired phenethylamine. 

Since the present patent proves that a CTH reduction of an aminoalcoholester-HCl salt can occur in water, just about any aminoketone-HCl salt should effectively be reduced to the aminoalkane-HCl salt as well.  This would eliminate the need to basify the aminoketone-HCl and risk pyrazine contamination.  Instead, the aminoketone-HCl from the former hexamine reaction could simply be used immediately.

What do you all think?

BTW, Rhodium. Have you checked out the only reference listed in the CTH patent?  I think YOU particularly will find it most interesting as you once mentioned that you were having trouble figuring out how to synthesize a certain p-flouro compound.

[Ritter]

Hi Regis,

That is a beautiful rxn. scheme if I have ever seen one, thank you!  We need more fresh posts from people like you around here to break up the monotony of watching the same themes get rehashed time after time.  Even if people don't respond to your posts publicly, TRUST ME, there are people out there who greatly appreciate and benefit from your work.
Thanks Again!

[GC_MS]

Here is another patent: Preparation of arylnitroalkanols, J Kamlet (Henry reaction is sometimes referred to as Henry-Kamlet reaction):

Patent US2151517

I have an article wandering around somewhere about the synthesis of ephedrine analogues via the nitroso route. I'll try to dig it up.

EDiT

Might be helpful: V Bruckner, A Kramli; Über eine Synthese von Ephedrinabkömmlingen. Arch Pharm 273 (1935) 372-384. Some parts of the synthesis refer to another article by Bruckner: V Bruckner; Liebigs Ann Chem 518 (1935) in press. I don't have this one though...

EDiT 2

Stupid me... V Bruckner; Über die Verwendung der Pseudo-nitrosite propenyl-haltiger Phenol-äther zur Synthese von alfa-arylierten beta-hydroxylamino- un beta-amino-propanolen. Neue Beiträge zur Kenntnis der Acylwanderungen. Methyl-isoeugenol- und Isosafrol-Derivate. Liebigs Ann Chem 518 (1935) 226-244.

Now, that's what I call a long title  

WOMAN.ZIP: Great Shareware, but be careful of viruses...

[Barium]

Super-easy preparation

10g 2,4-dimethoxybenzaldehyde (60mmol)
5,25g nitroethane (70mmol)
30ml 90% EtOH
250mg potassium fluoride (4,3mmol)

In a 250ml rb flask with a stirbar is added 10g 2,4-dimethoxybenzaldehyde and 25ml EtOH followed by nitroethane diluted with the remaining 5ml EtOH, then finally the potassium fluoride in one portion. The suspension is allowed to stir at room temperature for 2 hours, or 30 minutes after everything has gone into solution. The solution is then decanted from some insolubles and then diluted with 100ml water. This causes a clear yellow oil to fall out. Most of the water is poured off and another 100ml water is added. Within 10 minutes the oil crystallizes to a beautiful light yellow mass.

Yield: 13,24g (54,9mmol, 91,4%) 1-(2,4-dimethoxyphenyl)-2-nitropropan-1-ol

While I wrote this another reaction was running in the background...here it is

1-(2,5-dimethoxyphenyl)-2-nitroethan-1-ol

10g 2,5-dimethoxybenzaldehyde (60mmol)
4,25g nitromethane (70mmol)
30ml 90% EtOH
200mg KF

The reaction was performed exactly as the previous one. Within 45 minutes the reaction mixture was a dark yellow clear solution, at this point 100ml water was added which caused a dark yellow oil to fall out. Within 5 minutes this oil solidified to a dark yellow crystalline mass. The yield is not known at this point but it looks every bit as good as the previous reaction.

Catalytic hydrogenation freak

[GC_MS]

Why KF? I know lithium, sodium or potassium are used in the nitroalkanol synthesis, but is there a reason why you choose for the F^- salt? Would NaF, NaCl or KCl work equally well?
WOMAN.ZIP: Great Shareware, but be careful of viruses...

[moo]

The F^- ion is a weak base and serves the same purpose as other bases in the Knoevenagel condensation.

Edit: Oh yeah, this wasn't actually a Knoevenagel condensation. Still, that's what the KF is used for.

[Barium]

Yup, the KF is the weak base needed to induce the Henry condensation of the aldehyde and nitroalkane.
Catalytic hydrogenation freak

[Barium]

Slick ´n easy  


10g 1-(2,4-dimethoxyphenyl)-2-nitropropan-1-ol (41 mmol)
5,2g Zn (80 mmol), activated with 5% aq HCl for 2 minutes
6,3g ammonium formate (100 mmol)
40ml 90% EtOH

To a 250ml rb flask with a magnetic stirbar containing 40 ml 90% EtOH the nitroalcohol and the activated zinc was added in one portion at room temp. Stirring was started and the ammonium formate was added in three portions over 5 minutes. The temperature rose to 55 deg C within a couple of minutes but no cooling was applied and the exotherm was allowed to run its course.
When the temperature returned to 25 deg C the almost red solution was decanted from the remaining zinc and transferred to a separatory funnel. 50ml toluene and 250ml water was added and the pH was lowered to 2 with conc HCl. The aqueous layer was extracted with another 50ml portion toluene. The bright yellow aqueous phase was then made alkaline with NaOH which caused a yellow oil to fall out. The aqueous phase was then extracted with 2x50ml toluene, the toluene extractions combined and dried over MgSO4 and the solvent removed in a rotovap. The residue is a clear yellow oil weighing 6,3g. Crystallization will be performed later.

Yield 6,3g 1-(2,4-dimethoxyphenyl)-2-aminopropan-1-ol (30mmol, 73%)   
Catalytic hydrogenation freak

[Barium]

Look what I found  


Tet. Lett. No. 35, pp 3219-3222 (1978)

Nitroalkane synthesis, a convenient method for aldehyde reductive nitromethylation

The ability of fluoride ion to form very strong hydrogen bonds as HF₂^-, together with our expectation that the nitromethane condensation would proceed rapidly in protic solvent, led us to explore the use of potassium fluoride in IPA. In practice, we found that condensation of nitromethane with aldehyde proceeds rapidly using potassium fluoride (0.05 eq) in IPA (0.5 M), forming beta-hydroxynitroalkanes in high yield. This condensation can be further accelerated by adding a catalytic quantity (0.05 eq) of 18-crown-6.

Following the condensation, the solvent is removed leaving nitroalcohol, usually as the only detectable product. Acylation proceeds rapidly with acetic anhydride using 4-dimethylaminopyridine as a catalyst (25°C, 30 minutes). Forming of the acetates using 4-dimethylaminopyridine is superior to concentrated sulphuric acid as catalyst. Finally, reduction of acetates occurs uniformly with sodium borohydride in EtOH forming the nitroalkanes. The experimental details are illustrated for the conversion of 2-cyclohexenylacetaldehyde to 3-(2-cyclohexenyl)-1-nitropropane.

To a solution of 2 mmol aldehyde in 2 ml IPA was added 0.1 mmol potassium fluoride and 4 mmol nitromethane. After 6 h at 23°C, tlc showed one spot for the nitroalcohol at R_f 0.20 (silica gel, CHCl₃). The solvent was removed at aspirator pressure and replaced with 4 ml dry Et₂O. A mixture of 2.5 mmol acetic anhydride and 0.1 mmol 4-dimethylaminopyridine was added. After 8 h at 23°C formation of beta-nitroacetate was complete (R_f 0.59; silica gel, CHCl₃). Finally evaporation of the ether and addition of 4 ml 1M ethanolic sodium borohydride with stirring for one hour completed the sequence. The mixture was acidified with dilute hydrochloric acid, extracted with ether, and the crude product was purified by column chromatography on silica gel to give 78% of the desired nitroalkane.

Edit: Full article in

Post 442875

(Rhodium: "One-pot Reductive Nitromethylation of Aldehydes", Novel Discourse) /Rhodium

Catalytic hydrogenation freak

[Barium]

Patent EP0960876

Catalytic hydrogenation freak

[Rhodium]

I really like that reductive nitromethylation of aldehydes! It is a three-step one-pot procedure, something that I haven't seen much of in the literature. Do you think it would be possible to take it further than that to the phenethylamine with Red-Al or some CTH, making it a reductice aminomethylation?

[Barium]

If the nitro group is reduced in the presence of one eqvivalent formaldehyde - voila N-methyl whatever. Zn/HOAc is known to accomplish this. I dont know about the yields but I can look them up.
Catalytic hydrogenation freak

[Barium]

10g (60 mmol) 2,4-dimethoxybenzaldehyde
4.27g (70 mmol) nitromethane
200 mg KF
15ml IPA

All added to a 50ml rb flask and has been stirring for three and a half hours now. In the beginning it was a thick suspension, now it´s a clear yellow solution. I don´t have time to do a tlc right now (have to run), but from the looks of it it´s almost complete. Damn I like these small volumes of solvent   
Catalytic hydrogenation freak

[Ritter]

Barium & Crew,

Does anyone know if NaF is a strong enough base to catalyze the Henry reaction the same as KF?  If not, then there's only one way to find out...."Experiment is King"

[psytech]

I looking at the article on Rhodium's page, i can only see where they cited 1g 10% pd/c. Now if the procedure is scaled up. How much 10% pd/c would be used.

[Barium]

Do you think we know all the articles on his site by hard?
Which procedure are talking about?
Usually it is enough with 5-10% w/w catalyst/substrate

Edit
I read the article again and realized they actually don´t mention how much catalyst they used.
Fuckers!! Well as I said earlier 5-10% w/w will be enough.

Catalytic hydrogenation freak

[Ritter]

Barium,

Please check out: Tet. Let. 29, 5733 (1988)

This is a reference for a CTH of the nitroaldol from nitroethane and benzaldehyde producing PPA in 87% yield!!!  Hydrogen donor is HCO2NH4, Pd/C in methanol.  I don't have access to this article, someone PLEASE check it out!

[GC_MS]

I wanted to synthesize some aspirine the other day, using the following igredients:
- 11.5 g 3,4,5-trimethoxybenzaldehyde (M = 196.2 g/mol, purity > 98%)
- 5 mL nitroethane (M = 75.0 g/mol, d = 1.05 kg, purity > 97%)
- 30 mL EtOH (absolute)
- 168 mg NaF (M = 42 g/mol, purity > 99%)

I brought some of the 3,4,5-trimethoxybenzaldehyde in a RB flask (250 mL) and added 15 mL EtOH. I then added 5 mL nitroethane, followed by another 15 mL EtOH. I dropped the magnetic stirbar in the RB and while stirring, the NaF was added. After half an hour of stirring, it looked clear to me that the 3,4,5-trimethoxybenzaldehyde dissolved very slowly, so I heated the RB a little bit (a little bit, i.e. not refluxing). After another 2 hours, I stopped the stirring. The 3,4,5-trimethoxybenzaldehyde was dissolved completely, the reaction mixture was pale yellow in colour. I then decanted the reaction mixture in 100 mL cool demineralized water. Pricipitation commenced (PREP1). I decanted the water in another 50 mL cool demineralized water where precipitation continued (PREP2).
PREP1 was hard and yellowish white in colour. PREP2 was bright white. I dissolved some crystals in iso-octane and injected a 1 µL amount on GC/MS. The resuling chromatogram and mass spectrum are shown in the following figure.



As you see, the main peak (there is only one, you cannot miss it) is a compound with M⁺ = 196 amu. The mass spectrum gives a 1% match for aspirine, but a 98% for 3,4,5-trimethoxybenzaldehyde   .
I don't know how to give these data a good interpretation... Or it is my failure (has been several months since I performed an organic synthesis), or NaF cannot be used. I'd appreciate it if another bee tries it out as well.
geh in die knie. wackle mit den hueften. klatsch in die haende. und tanz den mussolini.

[Rhodium]

3,4,5-TMNS is supposed to be neon yellow. NaF had too low catalytic activity.

[Barium]

He didn´t try to make 3,4,5-TMNS but 1-(3,4,5-trimethoxyphenyl)-2-nitroethan-1-ol
Catalytic hydrogenation freak