ahm, this is quite awkward...
Does anyone have any real world experience with the so called "wet reductive amination"? the reason I ask is that for me and for *ALL* the chemists I personally know this has never worked. the wet red.amin always failed, for P2P, MDP2P, 2,5-diMeOP2P, using both commercial aq. methylamine and ethylamine, and concentrated aq. solution prepared insitu from the salts of both these amines.
to me this procedure is 100% bullshit and anyone saying it works implies either talking out of his ass or just plain dumb.
If anyone can produce actual proof of validation, be my guest and prove me wrong, but to all you newbies here : WET REDUCTIVE AMINATION WITH BOROHYDRIDE DOES NOT WORK . dont waste your time and precious reagents on it. Be prepared to do it as close to anhydrous as you can and you will get good yields!
It is possible that some variation of this, which isnt explicitly described in the HTML does work, but as it is written, I assure you, you will be dissappointed!!
If you wish to generate something close to an anhydrous solution of amines ready for reductive amination Ive always found the following to work well -

Take your aq. amine solution and measure out the amount you need. calculate how much water is in there by weight (so 100ml 40% MeNH2 solution has 60g water and 40g MeNH2 (1278mmol)). For every 1g of water you have, separately weigh 5g or more of dry NaOH (or KOH). For 100ml aq. MeNH2 you need 300g dry NaOH or more (I say or more because here more is better).
Take your solvent of choice and place 10 times the volume of aq. amine solution (so for the 100ml solution we have, we use 1L of solvent).
(I usually use toluene because it is so available to me. the amines have a low solubility in it compared to diethyl ether, so that might be a better choice and could help reduce the solvent amount needed.)
Cool the toluene in an ice-bath, add the NaOH dry, then add the aq. amine solution slowly (pour it by hand carefully, minding the temps - you want to keep it low as possible to avoid any amine loss). cork it and swirl it around. if you have 3A mol-sieves, add them freely (not nesscery, sometimes i add sometimes i dont). let sit for 30 minutes, swirl once more and then give 10 minutes to settle.
Decant the organic phase from the bottom dry/wet layer into your reaction flask. cool it in an ice bath. add your ketone slowly dissolved in methanol (1:4-5) while stirring. use a ratio of 1.2-1.5 molar equivalent of amine for 1molar eq. of ketone (100ml 40% MeNH2 = 1278mmol amine -> 1065mmol ketone). once all the ketone is in remove from ice bath and stir for 45 minutes.
Replace ice bath and add 0.5-1mol eq (relative to ketone) of NaBH4 in small portions with good stirring(amount depending on the quality of your borohydride). temps should not get above 15degC! if you can keep it at ~10degC it is best. Once all the nabh4 is added, keep stirring with the ice bath for 30 minutes more, then remove it and continue stirring for few hours more. if you can TLC, do it and stop the reaction when most of the ketone is gone. quench with either water or acetic acid, slowly. workup as you would like (a/b, steam distill, whatever). If done correctly, yields for both mdp2p and p2p with various ketone is routinely over 85%. with the common amines, if all is well, the average is ~90-92% yield, of distilled amines.

TroubleShooting :
1. Care should be taken to not have any base carried with the organic solvent! ketones + base can lead to polymerization. this is evident by the development of rich colors. for me the colors varied on the red colors whenever i failed to realized there was base present carried over from the drying step. If you see vivid colors, you should know that this batch will not yield well, and be aware of the reason! I suggest doing a small batch at first to get comfortable with the decantation. You can also let it sit before pouring longer to make sure everything has settled.
2. If temps while drying get too high alot of the amine escapes creating a deficiency in the amounts needed for full conversion! this is evident in tlc with the eventual halting of disappearance of the ketone. either make more amine solution and add it slowly, or halt reaction workup and recycle the leftover ketone. Be mindful of the temps!.
3. if your ketone and amine are clean to begin with, colors of the reaction will be pale and insignificant.
4. I always recommend purification at the end with whatever seems suitable. Vacuum distillation is by far the easiest way to purify isopropylamines in bulk. Get yourself a vacuum distillation station (preferably with a variable reflux head) if you respect yourself!.
5. Wet reductive amination have NEVER worked for me. Ive spent lots of time and reagents trying to make it work, never got it to. maybe my skills are lacking, though i doubt it. several chemist friends who have tried their best at making it work have also failed.
6. for the mathematically-disabled persons : for every 1mol of ketone (178.18g mdp2p) use 94.8g-118.5g (105.7ml-106.3ml) of 40% aq. amine, with ~1L of toluene (or other solvent) and 284.4g-355.5g of NaOH to make the dry amine solution.

Hope this helps

Fluorine is generally weakly deactivating, that could make all the difference  So far, if anyone has gotten this working with substrates of interest they haven't made their work public  Methods have been posted for preparing anhydrous methylamine gas 

Methyl Man, some sodium borohydride reductions can proceed in water. nitroalkene double bond reductions proceeds well under aq/organic bi-phasic ptc conditions. some SBH reductions of ketone to alcohol proceed well in water.
If you would look at the mechanism for imine formation (easily found with a search engine) you would see that water, H2O, is a product of one of the equilibriated steps.
this means that excess of water shifts the equilibrium to the right (meaning back to starting reagents) and reaction is slowed!
some sort of help is needed in order to make it work under aq. conditions, and as lugh said, the fluorine atom's electronegativity may be a contributing factor.
Like i wrote above, this has never worked for me and for chemists i personally know (as opposed to anonymous forum members) with the ketone that generally interest this board.
If you have access to chemicals, and you can get n-methyl-n-benzylamine (or n-ethyl or just benzylamine for non alkylated versions), use that as the source of amine in the reductive amination (these are available as dry products and are much less conspicuous then methylamine), followed by a quick hydrogenation of the benzyl group with Pd catalyst. This is usually done with a chiral amine to induce chirality in the final product (i.e. using (R)/(S)-n-methyl-1-phenylethanamine), but works equally well with non chiral amines.

Back on the matter, dont waste your time/money/reagents on the wet amination. as beanhead explained yields are horrible to non existent and this is just plain frustrating.

Here're another few important tips for aspiring new alchemists - Dont Take Rhodium's Archive To Be Gospel! Some stuff works some doesnt. ive had the dis/pleasure of trying out many many reactions and im telling you, not everything works as advertised. And even some of the stuff that works require heavy tweaking to make it work.
Be mindful of the references. whenever you see a reference which is Indian/Chinese in origin, begin to doubt the procedure. If possible read the original reference article and look for obvious errors. Look for experimental data on all products depicted in the articles. Those lacking in physical data (1H/13C-NMR ppm values, IR spectra, MS, etc...) are less reliable.
Know that internet myths and anonymous posts can be and sometimes are BS! people sometimes like to boast online, or flat out lie.
Know the mechanisms of your reactions to understand what is logical and what is absolutely not.

im sorry for the long posts, but this is one matter ive always been pissed about. there are just too many bunk procedures floating around on the net (maybe on purpose?). Ive lost lots of time and money trying out various procedures with various reagents and starting materials. Now that im a real life chemist as well I can also say that even the scientific literature is full of less-then-acceptable quality articles, so anonymous internet posts are sure to be plagued with lower quality information.
I never understood why some people on famous forums, like the hive for example, would seem to sometime just invent things out of thin air and posting it as if it works on all substrates. always seemed weird to me that someone will knowingly choose to do so without having an agenda which is not fitting of a drug synthesis forum.

I think it is a mixture of a poor peer review system (ive even seen an article with blatant typing errors in the data go into Nature only because the author is a close friend of the editor. sure it was later corrected, but the damage was done), and a publish or perish concept of academia. If youve worked in academia, everyone knows someone who is "cheating". it is a disease. the reasons for it, who knows?

The by far most common annoying thing i find in indian/chinese articles is how they put a table with a list of about 20 compounds undergoing the reaction with good yields, yet it is obvious (if you look hard enough) they only tested it on 1 or 2 substrates and then said, oh yea it works on the rest just as well, because why not... To me, if the experimental data of an article doesnt include physical data such as NMR, IR, MS, BP, MP, etc..., i dont believe it was made. sure this can be forged as well, but if they went through the trouble of doing a really nice forge, then kudos to them.
Another error ive come to encounter is indeed lack of proper techniques, or at least lack of proper documentation. Sometimes even reputable scientists leave out crucial parts of the writeup because it is obvious to them and all those around them. it is always important to inspect the procedures well and thinking about them logically, if it makes sense or not.

also, sometimes you go through an article, and you spot grammer (like this one) errors. sometimes you spot stupid sentences. sometimes you see that the pictures dont match the writing etc..., all of these are clues to having a poor or non existent peer-review system. You should be wary of such articles.

But like i said, the biggest tell tale of a problematic article is lack of physical data to support the claims. check out the supplementary data if available.
Also try to give more credit to articles coming from good reputable journals :
JACS, and Ange. Chem. are the 2 hottest journals right now.
Another good way to check out articles, is to try to find citations of the article at question in other articles. Most publishers offer this kind of search button to find where it was cited. if there are a few articles confirming the article or parts of it, written by various authors, then this serves as a point of confidence, that someone else has tried out this article and can "vouch" for its authenticity in a way.

Also, some authors are known and famous or semi famous (i.e. famous to nerdy organic chemists working in white lab coats all day). those you can trust. if you are mindful of the articles you have tested and their authors you can build your own "database of confidence" of authors and journals.

hope this helps!

Toluene is less hydrophilic, that's why it's been used in imine isolation procedures in the past 

if you read the procedure methanol is added to cosolve the methylamine and the ketone and the sodium borohydride.
i think it is just more convenient than setting up for gassing.
but if that reaction were to be done on any kind of scale i would think plan b would be best.

I tried the gassing method twice.

The first attempt the methylamine was bubbled into methanol at 0C without any problems and the ketone added and allowed to stir for 2 hours. NBH was added in portions over 8 hours and stirred for a couple days. A red oil fell out of solution but after cleaning and gassing nothing ever crystallized. Maybe I should've used more NBH? But when HCl was added it bubbled vigorously so I figured after 2 days and there's still NBH it must be done but no such luck.

The second attempt the gas for some reason would not bubble, I think my NaOH solution may have been too concentrated because I tried dripping it in slowly and nothing would happen. I left it for a bit and came back and it had sucked back all of the methanol, filling the flask with the methylamine and the flask I was using for a trap. After dealing with that stanky messy bitch I said fuckit I'm sticking with the Al/Hg.

So I think your idea sounds interesting. But testing out different solvents will be a pain.

Letters: thanks for those ideas, but I should point out that I'm not in the position you think I may be. Let's call me a hobbyist. I don't have access to all kinds of chems. I shrink from having to purchase things that I don't absolutely need for what I'm doing. I do have some NaBH4, and that's why I am trying to find a way to use it. I realize I will need the fish-stinky amine, but I'm willing to make it and fortunately it's within my abilities to do that from what I can tell. Already have of course NaOH and HCl and all those common things. I sure don't relish switching methods and getting used to the idea of a whole different set of chems I would have to find a way to buy. And yes, sodium methoxide and sodium metal etc is beyond what I should be messing with. I have no desire  to do anything like that (however I look forward to making PdCl2 out of Pd metal... that sounds fun and easy).

Are you saying there's no way it can be done anhydrously with the salt form of methylamine? Being a salt doesn't bring water with it, correct? It only brings the HCl aspect. Is there no way that uses the HCl salt in anhydrous MeOH (or whatever)? Is there no way an amine salt can be dissolved in an anhydrous alcohol, or dissolved in an alcohol and the resulting solution made anhydrous? If gassing MeOH with anhydrous methylamine is the ONLY way to get this done, then I will learn to do it, but I need someone---no, multiple independent someones---to tell me that there is absolutely no way to do it the way I'm talking about before I eliminate it.

These days, if I were forced to do an Al-Hg reduction, I think I would just do the methylamine one from TS2. But I don't really ever want to do the nitromethane version again, and am actually trying to avoid altogether methods using Hg (had an accident 10 years ago, and am now a bit Hg-shy).

So, my latest question appears to be:

Is there no way to do the NaBH4 reductive amination in which the methylamine HCl involved is dissolved in an anhydrous alcohol (or dissolved in an alcohol and the solution then made anhydrous) to prepare it for its addition? And if there is, in doing it that way, is the NaBH4 also dissolved in an anhydrous alcohol?

thanks
MM

I dont think it is disinformation on the boards as much as it is straight up memory impairment from insane doses of a certain something..

If ones synth works out and you follow it up by dumping a gram of what you made then wait a few years and have to repost and explian it, you might miss a thing or 2.. everything seems easy after you do it though, it seems once you do something once you cant believe how easy it was. Same with buying chems. Once you got them you think how much easier that was than trying to make it!

you are attempting a difficult enough synth as it is you dont need more variables like half pure precursors from making them yourself and the time and effort is really just worth finding a way to buy them you relly need to try harder search the chems, and trully believe your own bullshit about why you want them.

May i ask Methyl Man why you are turned off the nitro Al Hg??

Is it because of the heat and hard to control nature of it? id rather that than have to make methylamine, wouldnt you?


Also recently i tried gassing a dry naptha/toluene mixture no crystals would come.. till i salted them out with Ipa and MEK in the freezer for a day..

the naptha/toluene ipa mek went a wicked purple blue colour.. the crystals formed were too acidic and there was nothing i could do.. dont think gassing in naptha works too well.. it titrates dry, as it is supposed to but crystals dont want to fall out which is why i ended up over gassing it.. i should have done it slower and monitered the ph till 6 then just did the dual solvents. im not prepard to test it again

next will be extract with dcm a few times, wash it w water and brine, titrate the ph to 6, dry it MgSO4 strip off the dcm or evap it, then using old reliable IPA MEK dual solvent system in the freezer to get my crystals

Lugh wouldn't it be possible to have an alcoholic solution of Methylamine.HCl in one beaker and an alcoholic solution of NaOH in a separate beaker, and simply combine the 2 solutions with stirring to create the imine?