I'm working on writing up a specific step-by-step method for a NaBH4 reduction of our favorite ketone that is based on the "Wet NaBH4 reductive alkylation" paper found at Rhodium. As always, I need to work up a writeup in my own words to feel comfortable trying a new thing, and that's what I'd like to do here. This reduction (non-anhydrous NaBH4 approach) seems very elegant and straightforward.

What I'd like to ask of you guys with this post is help in ironing the wrinkles out of this approach as I apply it to the substrate I'm interested in. The original information concerns the reductive amination of 1-(2,4-dimethoxyphenyl)-2-propanone which produces 2,4-Dimethoxymethamphetamine, but---due to all the coaxing and coaching of Strike---I'm optimistically assuming that all of its "chemico-kinetics" will apply to MDP-2-P and MDMA as well.

First as a refresher I'll post the original, which I am basing my effort on, then I will post my work-in-progress, the re-imagining/transposition. I would appreciate greatly any and all insightful comments that could improve the writeup.

The original:

Improved "wet" reductive alkylation
(from Rhodium)

Chemicals Used:

* 1-(2,4-dimethoxyphenyl)-2-propanone (250 mmol, 1 molar equiv.)
* Methylamine HCl (375 mmol, 1.5 m.eq.)
* NaOH (375 mmol, 1.5 m.eq.)
* Sodium Borohydride (145 mmol, 0.58 m.eq.)
* Isopropanol (IPA)
* Water

Procedure

To a solution of 1-(2,4-dimethoxyphenyl)-2-propanone (48.56g, 250 mmol) in 300 ml IPA was added a solution of methylamine hydrochloride (25.3g, 375 mmol) in 30 ml water followed by dropwise addition of a solution of NaOH (15g, 375 mmol) 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 sodium borohydride (5.5g, 145 mmol) in 20 ml water containing 25 mg NaOH (to prevent decomposition) 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 2M hydrochloric acid (1:5 37% HCl:H2O) 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 2,4-Dimethoxymethamphetamine HCl (79%).


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The Methyl Man Edit (Unfinished! Working title. This is not a final version, this is a "raw" text on the table for improvement by committee):


To a stirred solution of 48.5g ketone in 300 mL IPA in a 1000 mL RB flask is added a solution of 25.3g methylamine hydrochloride in 30 mL distilled water.

Then without delay a dropwise addition is begun of a solution of 15g NaOH in 40 mL water during 10 minutes while stirring the mixture rapidly.

When the addition is complete, the stirring is decreased a bit (say, from high to medium) and the mixture is stirred briskly for another hour at room temperature.

A solution of 5.5g sodium borohydride in 20 mL distilled water containing 25 mg NaOH (to prevent decomposition) is then added dropwise over 30 minutes while the mixture is again stirred rapidly.

When the addition of the NaBH4 solution is complete, the stirring speed is dialed down from rapid to medium, and stirring is continued for two more hours.

After stirring for the two hours, the addition funnel is removed from the setup, washed, and filled with 2M hydrochloric acid (1:5 37% HCl:H2O). The residual borohydride is then destroyed by cautious dropwise addition of the HCl until the gas evolution stops and pH 3 is reached (in other words when gas evolution begins to visibly diminish, start testing pH).

The alcohol is then removed by vacuum distillation.

When the alcohol has finished coming over, the heat to the distillation apparatus is turned off and the setup allowed to cool to room temperature. The vacuum to the glass is released, then the setup is dismantled.

The remaining aqueous solution is transferred to a separatory funnel, diluted with 100 mL water, then extracted once with 50 mL DCM to recover any unreacted ketone. This extract is appropriately labeled and set aside for future recovery.

The aqueous solution is then made strongly alkaline (pH 12 to 13) with 25% (aqueous) NaOH and extracted with 2x100 mL DCM.

The DCM extracts are combined and then washed with a small portion of water to remove trace NaOH.

The DCM extract is dried with MgSO4, then filtered. The DCM is then gassed with HCl to form the crude salt.

The salt is then recrystallised in IPA/acetone.

Yield: Who knows?

====================================

Immediate questions that I have:

1. Will this work well as it is? Or have I failed to see some major area where something will not apply?

2. Is there any problem with the way I have detoured from the original to use DCM instead of toluene as the extraction and crystallization solvent? Do you see any solvent/reagent incompatibilities?

3. I'm not quite understanding, in the original, why when they have the freebase oil dissolved in toluene they don't just crystallize from there. Why do they distill the toluene off only to redissolve the f/b oil in another solvent? What's the point? Purification? I mean, the post reaction matrix in the Al/Hg had way more icky stuff in it than I imagine does the post-reaction mix in this NaBH4 way, yet there was no second solvent trip there (in the Al/Hg)---as soon as the product was extracted into toluene, the tol was washed, dried and gassed... and it obviously works great.

4. You may notice that I increased the 2x50 mL extractions with toluene to 2x100mL extractions with DCM. The reason I did this is that I can't imagine gassing a mere 100 mL of solvent to salt after all my experience with gassing toluene which was something like 750 mL volume if I recall! How can only 100 mL of solvent hold what is theoretically twice the amount of crude salt? Well, I know it can hold it, but what I'm saying is that 100 mL seems an extremely small amount of solvent to gas. Is there any harm in using DCM, and double the amount (compared to the extractions in the source text)? Or should one not gas at all if going this way, and use a HCl titration approach? I'm open to titration, but ratios and method would have to explained to me a little better than I can find info about anywhere so far.

5. Finally, if there is a better way or better instructions somewhere for doing the NaBH4 amination, one that does NOT require a LabTop type bubbling/gassing type approach for introducing the methylamine, please do share it because I have searched and searched for such a text, and this one (the original above) is far and away the closest to what I'm looking for. I've decided that I don't mind having to make the methylamine HCl, as it seems inescapable, but after that I don't want the added thing of having to make gas etc. I would like to be able to utilize it as simply as it is described in the original paper above (i.e. tossing it into an addition funnel with some water).

Thanks in advance for your contributions!

MM

Hmm... but what about the passages in Total Synthesis II where Strike raves about how great DCM is as a crystallization solvent, how he loved to gas with it, etc.? I was basing the idea to use DCM mostly on that. I recall that Strike wrote that at the end of the gassing, some weird looking pink crystals start to form and that is the signal that it's done. I certainly don't have to use DCM. I just have some, and the TSII info seems to encourage it.

Mainly, I'm wondering why in the original paper they extract into toluene, only to then turn right around and distill off that toluene and redissolve the freebase oil in ethyl acetate? Why couldn't they have just washed, dried and crystallized that toluene extraction? Unless there is some important purification reason to do that, it seems like a lot of unnecessary work to me. Like I say, if the post-reduction toluene extraction after the messy nitro/Al-Hg can be washed and then gassed, it escapes me why they do the extra work in this NaBH4 reduction which has to be *way* cleaner...?

There is no reason you cannot gas with HCl directly into your toluene extraction after its been washed and driied.

Here are a couple good reads on the NaBH4 reductions
http://www.dow.com/assets/attachments/industry/pharma_medical/chemical_reagents/reducing_agents/sodium_borohydride_digest.pdf
go to the section on reductive amination and there are a scads of references with variations you might want to look at

This one is also great for coming to a better understanding of the RXN mechanism
http://www.scribd.com/doc/31479358/Reductive-Aminations-of-Carbonyl-Compounds-with-Borohydride-and-Borane-Reducing-Agents-–-Ellen-W-Baxter-and-Allen-B-Reitz-–-Organic-Reactions-Volume

MM, this method will definitely work on MDP2P.  Since MDP2P has a lower molar weight than the original compound if you just keep the numbers the same you'll be using a larger excess of NaBH4 which won't hurt yields, might even bump it up a bit.

5M HCl in IPA is 128 grams of dry HCl gas dissolved in 1L of dry IPA.  It fumes just as bad as muriatic acid if not worse, but the scheme they use is really nice.  Especially if you've got dry IPA (hello iso!) and ethyl acetate.  You don't have to use 5M, by any means, you can generate going by argox write up, although he does have a flair for the overly complicated.

IMHO either gas in toluene or buy the IPA/HCl solution

It's much easier to get high yields using LaBTop's borohydride procedure    He would then gas the DCM extract with HCl  The end results from the effort applied 

Thanks everyone for your participation  

So adjustments so far look like:

1)  Forget the DCM, use toluene
2)  Gas the toluene just like I did back in the bad old days

We're looking at the NaBH4 ratio as per pyramid's question and akcom's post above... do most here basically agree that the amount in the original writeup is okay, then?

But how about my #4 question above:  should I really try to bubble HCl into a mere 100 mL of toluene? That almost seems like a microscale hassle to me. My only experience is with gassing 750 or 800 mL volumes. Could I just use more, merely to have a larger volume to work with? I remember I used to get 18 to 20g yields of crude salt when gassing after the nitro Al-Hg and it would fill a 1-liter beaker up very thickly, it looked just like Cream of Rice™ hot cereal. That was in 750 mL of toluene, and with this NaBH4 way I might get, with some luck, a 70% yield so that would be around 33g of salt forming in only 100 mL of solvent? See what I mean, it seems like nowhere near enough solvent volume. Then again the original did say "Several times the acid addition had to be stopped and the formed crystals removed by filtration."---but that's something I'd rather not do. Wait, hold on... oops sorry they were titrating into the 200 mL of ethyl acetate, not the toluene.  So my question is, is it okay to just use a lot more toluene for the extractions? I'd like at least 400 if not 500 mL. How would you handle this issue if you were planning this instead of me?

As an aside, I had been assuming that another way that one could make the HCl-in-IPA was that one could add Y amount of muriatic to Z amount of 99% IPA, then dry the mix with drying agent. But maybe that's simply too much water for drying agent to take on? I'd like to know if that can be done, but I don't really need the answer in this thread. I've always liked the idea of a crystallization like this where I could just pour such a mix into the f/b oil in a large beaker, cover with plastic wrap, then cram it in the freezer for an hour or two, then collect my crude salt. Sounds much more pleasant than gassing.

Fuming and corrosive... excellent point. It may turn any soggy drying agent into mush. There I go again trying to invent fresh and dumb ways of doing things. Cool then, if I use that approach someday later on, I'll do it the established way.

Great news about using as much solvent as I want to, thanks.

I'll be editing this thing forthwith and will post the update so we can all look at it a final (?) time before I'm satisfied that it all looks okay. At that point, I will (A) run it and make sure it works as written; if it does, (B) "release" the writeup and see whether it learns to boogie like my last ones did or falls flat on its face. All these tedious questions are designed to prevent the latter from happening!

BTW labtop did not used DCM to gas out the amine with HCl, he used the DCM to extract the crude amine from the post rxn and then he distilled the freebase out of it, witch was added to acetone and then gassed to the final product.

LaBTop recommended on 11-8-2001 that the average member use toluene to reduce the odor around their lab but then posted that he preferred gassing in DCM in 22 L flasks on 3-18-2002 since it took much less time    Thus the best course would depend on factors that are unique to the situation 

Just remembered an important one:  exactly what is the gas that's being evolved when the HCl is dripped in to destroy the borohydride? Need to know in order to plan to manage it... if it's CO2, no big deal, but if it's HCl, I need to be ready for the funk.

You need to start doing your own research before you get yourself into real trouble:

h**ps://secure.wikimedia.org/wikipedia/en/wiki/Sodium_borohydride

h**p://onlinelibrary.wiley.com/o/eros/articles/rel0001/rs052/frame.html

 

It sounds like that part should be done outdoors, with a mask, and with a fan blowing a breeze across the workspace and away.

You could also do it in a fume hood, or under weak aspirator vacuum    Diborane is quite toxic   This solution was posted on the Hive long ago:

Simple Trap for Obnoxious Vapors

In many syntheses large volumes of HCl, HBr, oxides of nitrogen, etc. are evolved, and in crowded laboratories it is sometimes a problem to provide adequate hood space. The drawing illustrates a simple device which economically answers the question of vapor disposal. It can be readily constructed from ordinary laboratory equipment. It dispenses with the usual alkali trap or specially made glass traps, and at the same time frees hood space for other experiments. A 500-ml.suction flask is provided with a 2 hole rubber stopper and two 8-mm. glass tubes are inserted. The bent one goes almost to the top of the inverted flask. and the other one projects about 4-5 cm. above the side-arm. Usually a condenser is employed in such experiments and a stopper provided with a short bent tube is inserted into the upper end of the condenser, this tube being connected with the bent glass tube of the trap by means of a short length of rubber tubing. The exit water from the condenser is led into the side-arm of the suction flask and the straight tube is connected to the sink. The current of water effectively removes the vapors. It is obvious that a large side-arm test tube, a distilling flask or a wide-mouth bottle provided with a 3-hole stopper can be substituted for the suction flask.

Additionally, it is also obvious that if one wished to trap a larger amount of gas, this device could be scaled up easily using a 5 gallon plastic jug with a  plastic tube attached to the side. Devices of this type have proven effective in concealing the most obnoxious reactions from observation.


 

an alternative to that is an inverted funnel a large hirsh type oil funnel attached to a aspirator line going down a sink the funnel is clamped above the source of offending gasses this also works well
alternately a cut out plastic jug is suspended over the work with a line out to the aspirator if you need more space.