[Johte]

Seriously, trying to find a protocol for a simple reaction when it's enantio0selective this green bulls&$# that.

For starts, I shall be attempting to tetramethylate diamines of n = 3, 4, and 5. 

Reductive amination or Eschweiler-Clarke is the first question I present. Though looking at my labs list it seems we don't have formic, can I substitute the acid?

Also, don't have paraformaldehyde and I do organic on the side, fat-change of a Dean-Stark. How do I drive imine formation with 37% formaldehyde in water ( formalin )?

Also, no NaBH4 but we do have NH4BH4. Such hydrogen. I was thinking formaldehyde reflux in DCM with molecular sieves, but the water content of the formalin seems a little much.

Synthetic design advice much appreciated.

[discodermolide]

What do you have in your lab?
You won't drive imine formation with 37% aqueous formalin. You could always try and concentrate it.
Got any sodium cyanoborohydride?

[Dan]

Reductive amination or Eschweiler-Clarke is the first question I present. Though looking at my labs list it seems we don't have formic, can I substitute the acid?

No - think about the role(s) of formic acid in the reaction, and it should be clear why you can't.

Also, don't have paraformaldehyde and I do organic on the side, fat-change of a Dean-Stark. How do I drive imine formation with 37% formaldehyde in water ( formalin )?

You don't need to drive imine formation to completion because the imine reduction is irreversible. Formalin is routinely used for methylation by reductive amination.

Also, no NaBH4 but we do have NH4BH4. Such hydrogen. I was thinking formaldehyde reflux in DCM with molecular sieves, but the water content of the formalin seems a little much.

You need a reducing agent - do you have Pd/C and ammonium formate (or any formate salts for that matter)?

[Johte]

No - think about the role(s) of formic acid in the reaction, and it should be clear why you can't.

Saw one ref with acetic acid, thats the one that didn't make sense. Had to ask to be sure.

You don't need to drive imine formation to completion because the imine reduction is irreversible. Formalin is routinely used for methylation by reductive amination.

This is why I found frustration in finding references for just the basic reaction.

You need a reducing agent - do you have Pd/C and ammonium formate (or any formate salts for that matter)?

Ammonium Formate, yes. Pd/C, no.

[Dan]

Have you got any other hydrogenation catalysts at all? Pd(OH)₂, Pd, Pt, Pt₂O etc.?

Any other borohydrides?

If you have formate salts you can titrate them with e.g. HCl and generate formic acid for an Eschweiler-Clarke that way. It's cowboy, but it should work.

Why don't you just buy some formic acid?

[Johte]

Everything said before this was based off a incorrect inventory which did not include formic acid or sodium borohydride..

I know now for sure that I have formic, formalin, and sodium borohydride. However, I thought I read that NaBH4 is used in a second step and not one pot so I don't personally see how to get dimethylation on each N. The recommended one pots are for cyanoborohydrides. The only one I have is tetrabutylammonium cyanoborohydride.

So how should I proceed?


Frak me, I'm driving myself crazy. I've realized my mistake here and know what I need todo. Thanks Dan.

[Johte]

Okay, I don't like the references I'm finding. Sci-finder either gets too specific or two broad. Reaction search seems really flawed.

Anyway, does anyone have a detailed reference or protocol for eschweiler-clarke?

[Dan]

Okay, I don't like the references I'm finding. Sci-finder either gets too specific or two broad. Reaction search seems really flawed.

Anyway, does anyone have a detailed reference or protocol for eschweiler-clarke?

What do you mean by "too general" and "too specific"?

We are not here to do your literature searches for you. See if you can get training if you are struggling with SciFinder. I personally prefer Reaxys, so maybe give that a try if you have access.

You don't bake all cakes a the same temperature for the same time, but generally the Eschweiler-Clarke reaction is performed with excess formalin and formic acid (3-100 equiv of each) at reflux overnight. There are hundreds if not thousands of examples of this reaction in the literature.

Example: JOC 1956, 21, 1050 Link

[Johte]

I wrote a defending explanation but realized that it doesn't matter.

Sorry for asking for too much.