Author Topic: A really wet reductive alkylation  (Read 26736 times)

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Rhodium

  • Guest
Wet reductive alkylation only for N-alkylamines
« Reply #20 on: June 16, 2003, 05:34:00 PM »
For the new members in the audience I probably need to add that the above "wet" method is only suitable for use with N-alkylamines, such as Methylamine/Ethylamine and similar, the yield with ammonium chloride or other ammonium salts is very likely to be sucky.

Barium: However, as you are now pioneering a VERY novel method here using a PTC in the reduction, I believe it would be HUGELY interesting if you could take this method as far as to actually TRY this procedure on something like 10-20 mmol scale, using concentrated ammonia as the aqueous phase. What if the ketone is water-insoluble, and the imine is not? Then the ammonium imine can be selectively reduced even if only a fraction of the added ketone is present in the imine form!

If you decide to go as far as you can go with this idea (I'd love if you could do that), then you could run three 10 mmol experiments in parallell, using the conditions below, and analyzing the resulting alcohol/amine ratio when the starting ketone has disappeared:

1) Your above conditions, but with 2 eq 25% NH3 as the amine (Aliquat 336 is a pretty hydrophobic PTC)
2) As in "1" but using the more hydrophilic tetrabutylammoniumbromide (TBAB) or any other Me/Et/Pr/Bu combo.
3) No PTC, simply running the rxn as a well-stirred two-phase rxn, possibly adding a few drops low-mw PEG if the reaction does not go forward at any reasonable speed.

I guess you understand my reasoning - by choosing a more and more hydrophilic borohydride species, you are treating the ketone in the toluene layer progressively more gently, while hopefully reducing the imine at a reasonable speed, and therefore making it possible to actually reduce an unsubstituted imine using aqueous borohydride.

I don't have more than 25% hope to get more than 25% yield in any of the above reactions, but the time and precursors might be worth risking, considering the immense gain gotten in case you could get even something like a 40% yield of amine this easy. As the reaction conditiona are so mild, any ketone not becoming amine should instead quantitatively become the 2-ol, which in that case can be recycled - possibly in the same pot, by just oxidizing the non-polar toluene solution resulting from extracting the product amine with aqueous acid in the workup. The ketone is then distilled and reused.

Barium

  • Guest
Heh
« Reply #21 on: June 16, 2003, 06:14:00 PM »
Two souls same thought. Before I posted this new reaction is was actually looking for a hydrophilic Aliquat PTC. My memory tells me that there is one in this family which is hydrophilic as opposed to the rest of the family. I'll give your proposed systems a try too.


Rhodium

  • Guest
Pegs & surfactants?
« Reply #22 on: June 17, 2003, 01:57:00 AM »
Low molecular weight PEG's are pretty hydrophilic, and if surfactants (like the short-chain pyridine quats), even if not being true PTC's, will work, they are ubiquitous, so that might be worth a try if the "standard" PTC's does not work satisfactorily...

psytech

  • Guest
OH MY F*&%ing GOD!!!
« Reply #23 on: June 17, 2003, 01:58:00 AM »
This is truly one of the greatest advances in clandestine chemistry. Barium may I work for you :). On second thought I'll just bow at your FEAT, get it. Thanks you have made my life so much easier, you will never truly know. Benezaldehyde to ketone, now this, amines almost in one pot, hahahahaha, I love it!

LaBTop

  • Guest
Very clever !!!
« Reply #24 on: June 18, 2003, 12:58:00 AM »
At last my dream came true after more than 5 years.
A dedicated scientist who simply found a way around forbidden precursors (how clever, and brave) and solved at last the methylamine gas tripwire trap, where so many abandoned the method for too many risks involved.

And what a clever, elegant solution, your perfect way to form the methylamine gas in situ!
And no cooling needed anymore, and the formation of a separate imine solution, hats off!
And then the added value of all your novelties you already offered in the last months.

A true MASTER of the ART.

Your Hydrous PTC Imine Reduction has now officially replaced ALL my boro one pots, what a great step forwards, I feel immens pleasure this very moment, thanks to you!
I just uncorked a bottle of Icewhine to celebrate the wonderfull moment, so, congratulations to you!

I'm waiting in awe for what the future will bring from you to our collective mind, I must admit, I envy you to be able to do this research, I never had the guts to confront the law in my part of the world with what would be a sure head-on collission course.
They would find a way to tackle me, probably in some unsportive manner bending the rules. LT/ , [fuckin happy as hell]


lugh

  • Guest
Imine Hydrolysis
« Reply #25 on: June 18, 2003, 01:49:00 AM »

What if the ketone is water-insoluble, and the imine is not? Then the ammonium imine can be selectively reduced even if only a fraction of the added ketone is present in the imine form!




Since the most common characteristic classical reaction of imines is aqueous acidic hydrolysis to reform the carbonyl and amine compounds that originally formed the imine, it seems rather likely that the imine will have greater aqueous solubility than the ketone  :)




Barium

  • Guest
Thank you LabTop
« Reply #26 on: June 18, 2003, 12:14:00 PM »
Your kind words make me blush. It warms my heart to see a really competent person appreciate my work. I wish I could have a glass of wine with you.
For the future: I have a couple of really nice things almost completed in the lab. Hopefully those new goodies will drive the DEA mad. At least one of them will be extremly hard for the fuckers to control the production of.. (insert evil grin here)  ;)


Rhodium

  • Guest
More on sodium triacetoxyborohydride
« Reply #27 on: August 15, 2003, 01:37:00 PM »
Reactions of Sodium Borohydride in Acidic Media.
Selective Reduction of Aldehydes with Sodium Triacetoxyborohydride

By G. W. Gribble and D. C. Ferguson
J. Chem. Soc. Chem. Comm. 535-536 (1975)

Summary

Aldehydes, but not ketones, are smoothly reduced to alcohols with sodium triacetoxyborohydride, prepared from sodium borohydride and acetic acid in benzene.

Although aldehydes are generally reduced more rapidly than ketones by alkali metal borohydrides2,3 and aluminohydrides3,4 and diborane5, the absolute rates of reduction are too fast to take advantage of the inherent relative rate differences between aldehydes and ketones, thereby making the selective reduction of aldehydes impractical. Our recent report1 that aldehydes can be generated from carboxylic acids with sodium borohydride (leading to a new alkylation of amines1,7) suggested that aldehydes and ketones are in fact reduced relatively slowly by sodium borohydride in carboxylic acid media, and that a practical selective reduction of aldehydes was feasible.

Thus, treating a benzene suspension of sodium borohydride (4 eqv.) with glacial acetic acid (3.25 eqv.) and refluxing the mixture for 15 min under nitrogen, after the initial rapid gas evolution subsided (ca. 3 mol of H2 liberated), gave a clear solution of NaBH(OAc)38. To this solution of NaBH(OAc)3, (0.027 mol) was added an equimolar mixture of benzaldehyde and acetophenone 0.007 mol each), and the mixture was refluxed for 1 h.

Workup gave a mixture (87% recovery) of benzyl alcohol, acetophenone, and alpha-phenethyl alcohol, in the proportions (NMR) 100:92:8, indicating complete reduction of benzaldehyde but <10% reduction of acetophenone under the extreme conditions of, excess of, NaBH(OAc)3 in refluxing benzene.

A similar reaction with a mixture of phenylacetaldehyde and dibenzyl ketone gave a mixture (90% yield) containing only ß-phenethyl alcohol and recovered dibenzyl ketone.

On refluxing the benzene solution of NaBH(OAc)3 for 6 h, then adding benzaldehyde, only 8% reduction to benzyl alcohol is found. This is consistent with the self-reduction of NaBH(OAc)3 to ethanol via acetaldehyde as proposed1 for the amine alkylation sequence involving NaBH(OAc)3.

The remarkably mild reducing characteristics of NaBH(OAc)3 may be attributed both to the bulky nature of the reagent and to the inductive electron-withdrawing ability of the three acetoxy groups (I 0.39)9 which stabilize the boron-hydrogen bond.

Although acyloxyborohydride species have been sporadically mentioned in the literature5,8,10 the synthetic potential for these reagents has never been realized.

Notes and References

1 For previous paper in this series, see: G. W. Gribble, P. D. Lord, J. Skotnicki, S. E. Dietz, J. T. Eaton, and J. L. Johnson, J. Amer. Chem. Soc., 1974, 96, 7812.
2 H. C. Brown, O. H. Wheeler, and K. Ichikawa, Tetrahedron, 1957, 1, 214.
3 (a) For reviews, see: H. O. House, 'Modern Synthetic Reactions', 2nd Edn., Benjamin, Menlo Park, Calif., 1972, ch. 2; (b) H. C. Brown, 'Boranes in Organic Chemistry,' Cornell University Press, Ithaca, N.Y., 1972, ch. XII.
4 H. C. Brown, P. M. Weissman, and N. M. Yoon, J. Amer. Chem. Soc., 1966, 88, 1458.
5 H. C. Brown and B. C. Subba Rao, J. Amer. Chem. Soc., 1960, 82, 681.
6 For a review, ref. 3(b) ch. XIII.
7 G. W. Cribble and P. W. Heald, Synthesis, in the press.
8 This species has also been reported to be formed along with sodium diacetoxyborohydride, from triacetoxyborane and sodium hydride: C. D. Nenitzeseu and F. Badea, Bul. Inst. Poluch. Bucuresti, 1958, 20, 93 (Chem. Abs., 1961, 55, 2325).
9 R. W. Taft, N. C. Deno, and P. S. Skell, Ann. Rev. Phys. Chem., 1958, 9, 287.
10 T. Reetz, J. Amer. Chem. So,., 1960, 82, 5039; T. Wartik and R. K. Pearson, ibid., 1955, 77, 1075; J. Inorg. Nuclear Chem., 1958, 7, 404.

LaBTop

  • Guest
Let's speed up things.
« Reply #28 on: September 07, 2003, 07:02:00 PM »
Normal Hive reactiontime policy on groundbreaking novel procedures is up to TWO YEARS!

In this case, I really like to see results and reports from other daring members, to give this beautifull procedure the IMPACT it deserves around especially Newbees.
I just linked this thread in the Newbee forum sticky threads, where I thought it was already linked there by me at the same time I linked it in the sticky one in this forum.
Some one there intended to follow my old procedure again, can you imagine that?!

So feel free to add any own experiences with this method here. LT/


Barium

  • Guest
Improved "wet" reductive alkylation
« Reply #29 on: September 13, 2003, 02:32:00 PM »
1-(2,4-dimethoxyphenyl)-2-propanone, 250 mmol
Methylamine HCl, 375 mmol
NaOH, 375 mmol
Sodium borohydride, 140 mmol
IPA
Water


To a solution of the ketone in 300 ml IPA was added a solution of 25,3 g methylamine hydrochloride in 30 ml water followed by dropwise addition of 15 g NaOH dissolved in 40 ml water during 10 minutes while stirring the mixture violently.  When the addition was complete the mixture was stirred for another hour at room temperature.
A solution of 5,5 g sodium borohydride in 20 ml water containing 25 mg NaOH was then added dropwise over 30 minutes while the mixture was stirred violently. When addition was complete the stirring was continued for two hours. The residual borohydride was destroyed by addition of diluted hydrochloric acid (1:5 conc hydrochloric acid:water) until gas evolution ceased and pH 3 was reached. The alcohol was removed by distillation in a rotovap and the aqueous solution diluted with 100 ml water, extracted once with 50 ml toluene, made strongly alkaline with 25% aq. NaOH and then extracted with 2x50 ml toluene. The combined alkaline extracts was dried over MgSO4 and the solvent removed by distillation. The residual oil was dissolved in 200 ml EtOAC and 5N HCl/IPA was added in portions until pH 5 was reached. Several times the acid addition had to be stopped and the formed crystals removed by filtration. The salt was then recrystallised in IPA.

Yield 48,5g N-methyl-2,4-dimethoxyamphetamine hydrochloride (79%).


I discovered some time ago when performing CTH's using aqueous solutions of sodium hypophosphite, Pd/C and EtOAc to reduce phenylnitroalkenes to ketoximes that the reductions didn't start until a few ml's IPA was added. This shows that IPA can act as a PTC. It is also cheaper and more accessible than PEG's or Aliquat's.


Lilienthal

  • Guest
Maybe IPA acts as a hydride donor or carrier?
« Reply #30 on: September 13, 2003, 06:12:00 PM »
Maybe IPA acts as a hydride donor or carrier?

bio

  • Guest
Improved "wet" reductive alkylation
« Reply #31 on: September 14, 2003, 05:37:00 AM »
OK, LabTop and Barium.
I for one have used the wet method in the past but not with these groundbreaking results. Also have read with great interest about this method, in my short time on the Hive and have wondered why there seems to be limited interest. Will try it soon and post the findings.

Now, Barium if you could be so kind as to give me some hints on suitable Bayer/Villiger catalysts it would be much appreciated.

bio

  • Guest
Bayer/Villiger catalysts
« Reply #32 on: September 14, 2003, 05:52:00 AM »
Yes, I know that was incomplete but the other night I typed a long post and it wouldn't go through. So at least I know this is working now.

I started a little thread in Methods on the twodog procedure you might have seen. This is what I am doing now. With sucess I might add. He gave me some very helpful information and Rhodium also as well. As my access to the journals is unavailable at this time I am limited to the internet for guidance.

Barium

  • Guest
Sorry
« Reply #33 on: September 14, 2003, 02:38:00 PM »
I have yet no experience with the Bayer/Villiger reaction.


endo1

  • Guest
MDP2P
« Reply #34 on: December 03, 2003, 12:29:00 PM »
OK! So.. if someone had some MDP2P and wanted to use a "A really wet reductive alkylation," would the "Improved wet reductive alkylation" method be suitable?

Rhodium

  • Guest
yup
« Reply #35 on: December 03, 2003, 12:32:00 PM »
Yes - just correct for the differences in molar weight of the substrates.

Bond_DoubleBond

  • Guest
Scalable?
« Reply #36 on: December 16, 2003, 09:48:00 PM »
Can anyone who has performed Barium's NaBH4 hydrous reductive amination (3,4-MDP-2P or otherwise) comment on the scalability and temperature sensitivity (as it relates to increaced scale) of this reaction?

Specifically, swim is interested in how scaling the reaction should effect imine formation time, NaBH4 addition time, and the possible need for external cooling.

Thanks...and bravo, Barium.

andromeda

  • Guest
Interim Results
« Reply #37 on: January 07, 2004, 05:22:00 AM »
I have been trying to master Barium's wet method, have had mixed results so far but it is probably more due to errors on my behalf than anything else.

i have also been doing these trials scaled up (350g MDP2P) for a couple of reasons;
1) to achieve the prescribed optimum (violent) stirring in my equipment (anything less doesn't stir)
2) i want it to work at this quantity, so may as well try getting it to work from day 1.

Very briefly;

trial one failed due to mainly (i think) my mixing of NaBH4 with water and then the NaOH rather than basifying the water first?

trial two worked ok with approx 200g of MDMA.HCL yielded. (Naturally i am hellbent on increasing this yield but i was ecstatic on the fact that it worked...i am so sick of messy Al/Hg.)

trial three is partly processed but i don't consider at this early stage that it will be successful as trial two due to a strange blue color.

I will post more thorough details tomorrow and if i have complete failure, i will include some photos so that the experts can hopefully pinpoint the errors.

Rhodium

  • Guest
reuse the lost byproducts
« Reply #38 on: January 07, 2004, 05:56:00 PM »
Most of the MDP2P not converted to MDMA will instead have been reduced to MDPol, which will be left in the non-polar phase after the acid/base extraction. This can be isolated, distilled, and then re-oxidized (with chromate, bleach, etc.) to MDP2P and then reused.


Bond_DoubleBond

  • Guest
Rhodium, so swim is clear, is this correct for
« Reply #39 on: January 09, 2004, 09:14:00 AM »
Rhodium,

so swim is clear, is this correct for an a/b workup of barium's reaction to isolate both mdp2pol and mdma.hcl?

1. flood reaction contents with water.
2. extract with np.  will dcm be fine for mdma fb and
   mdp2pol?  swim wants to use a volatile np solvent.
3. acidify with aq hcl and separate (will acid only react
   with the amine and not the alcohol?)
4. continue a/b workup on aq phase to get mdma
5. evap np to get mdp2pol

will this produce sufficiently clean mdp2pol for oxidation?  or must (swim says must, not should) he vacuum distill as mentioned in

Post 399715

(Rhodium: "Piperonal -> MDP2NP -> MDP2P -> MDP2Pol", Novel Discourse)
?  swim asks because he has read many posts that say that mdp2pol rearanges and may be otherwise unstable.

also, is anything else created as a reaction side product other than mdp2pol using this method?  swim is trying to find out if anything else will be sucked into the np from the reaction mixture and be there when it evaps off.