Sciencemadness Discussion Board

Alternative to DCE or THF

rudy090992 - 7-11-2012 at 15:43

I'm interested in performing a reduction with sodium triacetoxyborohydride. However, the only solvents that the article refers to is DCE, THF and acetonitrile. What are some possible alternatives to a reaction like this? It looks as though aprotic polar solvents are key. Acetone won't work because of the carbonyl neither will mek


Here is the info for the article.

J. Org. Chem. 1996, 61, 3849-3862
3849
Reductive Amination of Aldehydes and Ketones with Sodium
Triacetoxyborohydride. Studies on Direct and Indirect Reductive
Amination Procedures1
Ahmed F. Abdel-Magid,* Kenneth G. Carson, Bruce D. Harris, Cynthia A. Maryanoff, and
Rekha D. Shah
The R. W. Johnson Pharmaceutical Research Institute, Department of C


[Edited on 7-11-2012 by rudy090992]

jon - 7-11-2012 at 16:15

anectdoctally ethyl acetate will work for this i have'nt dug too deep into it but that sounds like a convenient solvent.
this is anectdoctal information i got from another chemist.
so take that with a grain of salt.

rudy090992 - 7-11-2012 at 18:19

I believe DCM will do the trick but I'm not sure. DCE is the preferred solvent for the reaction followed by THF. Acetonitrile is less than ideal. The article doesn't mention DCM

DCM and DCE have similar dipole moments and dielectric constants and they are both aprotic.

It seems to me like DCM would be better than acetonitrile considering DCE is a good solvent but if that was the case then surely they would've mentioned it in the article.

DCM wouldn't react with sodium triacetoxyborohydride.

rudy090992 - 7-11-2012 at 18:21

I'm afraid that ethyl acetate would react with an amine in the presence of triacetoxyborohydride

DJF90 - 7-11-2012 at 19:02

I've used DCM as a solvent for the N-benzylation of anilines before, using STAB. Yields were dependant on the electronics of the ring (e.g. 4-NO2 did not seem to want to work, neither did 4-CF3), but I generally obtained 60%. Methanol was another solvent I've seen mentioned, due to rapid imine formation.

Another method you might wish to try is the pre-formation of the imine by stirring the aldehyde, amine and anhydrous MgSO4 in methanol overnight, with addition of NaBH4 to effect the reduction. Ethyl acetate should not react with an amine in the presence of triacetoxyborohydride, as you claim, but I also do not think it is as good a solvent as some other alternatives.

jon - 7-11-2012 at 19:12

or you can form the imine and dean stark it with toulene distill toulene and reduce with nabh4 in alcohol that works reliably.

jon - 7-11-2012 at 19:39
Quote:

textI've used DCM as a solvent for the N-benzylation of anilines before, using STAB. Yields were dependant on the electronics of the ring (e.g. 4-NO2 did not seem to want to work, neither did 4-CF3), but I generally obtained 60%. Methanol was another solvent I've seen mentioned, due to rapid imine formation.




i'm not so sure about that that would'nt work with stab you can't use protic solvents with stab it will decompose according to my understanding.
it will work with NaBH4 but you have to employ about 3 moles of NaBH4 to account for it's spontaneous decomposition in protic enviroments.

rudy090992 - 7-11-2012 at 20:02

This is straight from the article...."Solvents such
as water or methanol are not recommended. Reactions
in methanol resulted in a fast reduction of the carbonyl
compound, and the reagent decomposed in water."

So it sounds like aprotic polar is the way to go. I am particularly interested sodium triacetoxyborohydride because the article made it sound like it was an extremely efficient compound that didn't need extreme conditions.

DJF90 - 7-11-2012 at 20:17

Sorry, I must have got my wires crossed. I guess what I remember is that solvents like DCE and methanol favour imine formation. But like I said, I tried the reactions using DCM as the solvent and was not really impressed. Whether DCE would do better or not is unbeknown to me, as I didn't try it, but I'd suspect it must be superior as DCM would have likely been one of the first solvents they screened, and they wouldn't choose DCE over DCM for no reason...

I recall reading this paper at the time also, which someone has helpfully uploaded here: http://www.google.com/url?sa=t&rct=j&q=&esrc=s&a...

Note that several things are mentioned:
Quote:
We avoided the use
of dichloromethane despite its suitablity as a solvent, due to
its tendency to react with amines.43 It is also undesirable in
large-scale reactions because of its toxicity and volatility
which increase the chance of exposure.

and
Quote:
Reactions in methanol were not consistent,
and in many cases, particularly with aldehydes,
reduction of the carbonyl compound was competitive with
reductive amination. Several groups have used methanol
successfully as solvent in reductive amination reactions.44-46
Higher alcohols such as ethanol and isopropanol react
slower with NaBH(OAc)3 than water and methanol and may
be used as solvents.

jon - 8-11-2012 at 11:47

so ipa would be good except it does'nt facilitate imine formation because of it's pka yet when working with more reactive aldehydes it may be a non-issue.
ipa maybe t-butanol even because of it's shielded protons may be just the ticket i found out in some reactions like some sn1 sn2 reactions would be solvents of choice.

rudy090992 - 8-11-2012 at 13:57

You maybe right Jon, but I can't go down to the store and buy some t-butanol. Trading methanol for IPA still makes the most sense to me (if one were going to use an alcohol). You might get less imine formation but you also get less borohydride decomposition. Imine formation is also favored with the addition of a little acetic acid.

DCM has some history in these reactions but the yields seem to suffer. If you're willing to take the loss then DCM seems like the perfect solvent.

Lambda-Eyde - 8-11-2012 at 15:24

Quote: Originally posted by DJF90  
I've used DCM as a solvent for the N-benzylation of anilines before, using STAB.

Because I'm curious: What the heck is STAB? Google turns up only garbage...

Scr0t - 8-11-2012 at 16:08

Quote: Originally posted by Lambda-Eyde  

Because I'm curious: What the heck is STAB? Google turns up only garbage...


STAB == Sodium triacetoxyborohydride

jon - 8-11-2012 at 19:46
Quote:

TextYou maybe right Jon, but I can't go down to the store and buy some t-butanol. Trading methanol for IPA still makes the most sense to me (if one were going to use an alcohol). You might get less imine formation but you also get less borohydride decomposition. Imine formation is also favored with the addition of a little acetic acid.

DCM has some history in these reactions but the yields seem to suffer. If you're willing to take the loss then DCM seems like the perfect solvent.


just make sure your stoichiometry is on the mark with the acetic acid i would just use the acetate salt of the amine you might get that to work.

rudy090992 - 9-11-2012 at 13:26

Thanks Jon. I didn't even think to do that. However, I don't know if acetate will catalyze the reaction in the same fashion.

I'll look into it

jon - 9-11-2012 at 13:46

common knowledge in NaBH(CN)3 reductions you use ammonium acetate there is a certain ketone reduced like this, well digressing NaBCN3 is known as (shiff's base reducer) because of it's chemoselectivity.
but for good imine equilibrium over the carbinolamine you need it protonated to a certain degree if it becomes too protonated it beccomes a poor nucleophile because of the lone pair of electrons on the lets say ammonia molecule for ex. are covalently-ionically bonded now.
even when reducing certain ketones in the prescence of ammonium acetate over PtO2 you have to poison the catalyst a bit with dmso because the equilibrium is'nt all that far to the right.
just to give you an idea, so that the PtO2 (prereduced) does'nt reduce the ketone.

UnintentionalChaos - 9-11-2012 at 14:10

Quote: Originally posted by jon  
common knowledge in NaBH(CN)3 reductions you use ammonium acetate there is a certain ketone reduced like this, well digressing NaBCN3 is known as (shiff's base reducer) because of it's chemoselectivity.
but for good imine equilibrium over the carbinolamine you need it protonated to a certain degree if it becomes too protonated it beccomes a poor nucleophile because of the lone pair of electrons on the lets say ammonia molecule for ex. are covalently-ionically bonded now.
even when reducing certain ketones in the prescence of ammonium acetate over PtO2 you have to poison the catalyst a bit with dmso because the equilibrium is'nt all that far to the right.
just to give you an idea, so that the PtO2 (prereduced) does'nt reduce the ketone.



Sodium cyanoborohydride is NaBH3(CN) and does not have three cyanide groups

jon - 9-11-2012 at 14:40

i stand corrected