The use of sodium borohydride as a reducing agent of imines, while not new, is certainly somewhat novel. Most of us who've gone through formal organic chemistry training at a university have had it beaten into our heads that sodium borohydride is a poor choice for a reducing agent of imines. The logic was that sodium borohydride chemoselectively favored the reduction of more polar double bonds, and hence a side route would be prefered, where the imine would hydrolyze to its corresponding ketone and amine, then the ketone would be reduced to an alcohol. Sounds convincing -- especially when a PhD who happens to be a world's leading expert in natural products synthesis says it. In every textbook I've seen discussing the topic, this mantra -- NaBCNH3 good, NaBH4 bad -- is repeated ad infinitum. Thus, it was gently set aside, and other practical matters were discussed.
Then LabTop came along, and his empiracle data has blown that all out of the water.

So what gives? We have the opnion of virtually every synthetic chemistry PhD on one side, and the lab results of many, many bees on the other. Physical evidense wins out over opinion, but how does one explain this inconsistancy between current dogma and what has been empiracally proven in the lab?

What are the reasons behind this phenomenon? Is this a matter of kinetic-vs.-thermodynamic product favorability? If so, wouldn't an adjustment of reaction conditions (say, cooling the reaction down to -78 C) give even better yields?

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-the good reverend drone

 
KrZ
Member   posted 10-25-1999 09:30 PM          
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Seems like the imine reaction is pretty favored under the conditions which these people are supposedly using. It certainly isn't going to allow formation of additional imine after the NaBH4 is added, but I can see how it would be possible that what imine was present would be reduced. I've never tried the reaction myself. I've been strongly opposed to this reaction because of all the things you mentioned drone, I've read and read and see no indication that this should work well. I've also read about how NaCNBH3 scales very badly, and I've pretty much noted that in my own experiences with it in the reduction of legal chemicals. I can't really decide about this reaction, I can't bring myself to waste costly reagents on it just to find out if it works (especially since I have some highly successful methods for reductive alkylation already). Seems very suspicous to me, and I wonder what yields are really being obtained.
 
Osmium
Member   posted 10-26-1999 03:29 AM          
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The reason for all this, imho: by working in a pretty much dry solution, there is no way the imine could split up again. When there's no ketone around, the NaBH4 can't do its evil thing on it, and has to react with the imine instead.
Chemists, like the rest of humanity, are a bunch of lazy couch-potatoes. Somebody (ALDRICH), which happens to be the seller of a new expensive reagent (NABH3CN), writes an overview of its uses in a big respected journal like Synthesis praising the virtues of this wonderful substance. It costs a lot, but look, the results! Everybody takes for granted that NaBH4 doesn't work for that kind of chemistry, and that's it.

Xaja
Member   posted 10-26-1999 05:40 AM          
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I thought hydrides would be fine to reduce imines!
Is this the mechanism?:
The hydride donates H(minus) which attacks the electrophilic C in the imine bond, a pair of electrons from the C=N double bond jumps onto the nitrogen, the sp2 hybridised C becomes sp3 hybridised with the addition of the new H, and from there amine is formed.

MERLIN
Member   posted 10-26-1999 09:52 AM          
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Here are all your answers :
J. Org.Chem.,Vol.63,No.2,1998,pag.370-373.
One-Pot Reductive Amination of Conjugated Aldehydes and Ketones with Silica Gel and Zinc Borohydride.
Brindaban C.Ranu, Adinath Majee, and Arunkanti Sarkar.
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta-700 032, India.
Received June 19, 1997.
Lots of refs......
My method is much earlier discovered, seams those Indian guys had some contacts in my circles, or were a bit more innovative then the rest, they just made things a bit more difficult by converting NaBH4 to Zinc Borohydride. But they still did not got the real touch of it as you can see.
Notify the high yields and the use of Silica Gel, as Proposed by me in the One Pot d-l-Meth synth. The exclusion of water in all steps is very important to reach the high yields I got.
If someone wants this article, I can upload it to a proposed site, so you can all be enlightened.
I somehow feel a bit more affected to this new name/signature then the LaBTop-one.
And I do not react on nearly all emails to me, because it was the source of more then 100 stupid hacker attacks on my computers, got a bit bored with that, so the good ones had to "suffer" with the bad ones, until somebody will generously upload AVP (AntiVirusProfessional) to a site where I can download it from, so there will be no more keyboard monitors dropped in my system, which allow malicious intruders to read everything you type into things like hushmail, anon nymserver etc.
It is certainly a bad thing to know that an email I send to you is allready read by god knows who, do'nt you think so?
In my opinion these keystroke monitors are the biggest threat to members of the Hive momentarily, because all your efforts to communicate securely by Hush etc are worthless against them, and you can only find them with sophisticated programs, which most of you will lack. Nearly all AntiVirus programs can not detect them !
Please address this security leak in a new thread on the Couch, I'll find it, still reading everything, do'nt want this thread spoiled by ramblings about other (however evenly important) things.
Oh, and KrZ, you'r gonna try it now ?
Rev drone, thanks for the kind support, and deeper cooling (to -20 C) gave no better results, only the use of simple Silica Gel beads 4-5mm or MgSO4.7H2O (both thoroughly dried in an oven at 300 C for min 2 hours) both gave even better yields.
And surprisingly, when there was added not enough drying agent, you should expect that the equilibrium between imine and alcohol forming would favor the alcohol, but then adding more drying agent moved that again back to the imine, nothing lost, very surprising discovery. Strange synth, I agree wholeheartedly. Would like to hear more on the theory also, till now looks more like a miracle synth, without the proper theoretical background,to many of you.
So you see, there are still a lot of lazy PhD's out there, too lame to explore the unknown.
It's my opinion that the factors which gave result are:
1. Use GAS, GAS and more GAS
2. Use >98 % pure chemicals (the KETONE !)
3. Temp range between 7 and 20 C
4. Exclude ALL water in all steps,spec.imine!
5. Patience when adding NaBH4 !
Unbelievable, people need months to scrap all the necessary chems and materials together, take 25 yrs risks, and then want to safe TIME ! on the synth, fuckin morons !
And there is on the moment no higher yielding synth which can be upgraded ad infinitum like this one.
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WISDOMwillWIN

 
LaBTop
Member   posted 10-26-1999 02:03 PM          
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See above.....
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EMOTIONSwill always beFREE!

 
K.C. Nicolaou
Member   posted 10-26-1999 04:58 PM          
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Basically, every answer to rev drone's question that I have has already been given. That is, that NaBH4 will reduce imines, that the use of anhydrous conditions and an excess of amine is a requirement in order to push the equilibrium towards imine formation, that the reason that this isn't given as a method in classes is that NaCNBH3 is usually less sensitive to the presence of water, gives better chemoselectivity and most professors have more interesting things that they want to teach you than what is essential a very basic synthetic procedure. So what's my point? I just wanted to say that based on personal experience working with legal chemicals in a regular laboratory (I'm serious, not just trying to cover my ass), I know the following to be true:
1. NaBH4 can reduce imines cleanly and in very high yields.

2. It is very important to exclude water from the reaction to avoid imine hydrolysis.

3. Drying agents can be used in a solution of the ketone/amine to remove the water of condensation before addition of NaBH4(I used mol. sieves, I own a book that describes the use of MgSO4 in a synthesis for the same purpose, Merlin says silica gel is also acceptable). In-situ use of a drying agent may also be acceptable.

4. My reaction conditions were 0 degrees C, 50/50 THF/MeOH (Straight ETOH or MeOH is probably fine also), 2 molar eq. of NaBH4 (you can use less than this, but reaction time will be longer), reaction time of 30 min, yields were consistently in the range of 85-95%.

 
rev drone
Member   posted 10-26-1999 07:41 PM          
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Yes, I don't believe there's anybody contending that NaBH4 won't reduce an imine to an amine, but there's still this issue of chemoselectivity here. Look at the yields people are reporting with the alledgedly inferior reagent. As for simplicity, again NaBH4 wins out; sure adding NaBH4 by the quarter teaspoon is a drudgery, but compare that to testing and retesting the pH of a NaCNBH3-based reduction for hours on end. With all this going for it, still people put forward NaCNBH3 as being the most desirable choice in this matter.
I hate to be cynical, but I'm starting to agree with Osmium. It really looks like its a matter of ignorance and laziness.

When a grad student gets their PhD, they are covertly injected with a sophisticated neurotoxin during the graduation ceremony, which destroys the part of the brain that enables a normal person to say things like "I don't know", and "I'm not sure." The result is, when pinned to give an answer, they automatically will grasp at anything to cover up their infermity. "Well, yeah. Sodium cyanoborohydride is CLEARLY superior to sodium borohydride for reducing imines; every IDIOT knows that..." Sad, sad, sad. Next time you hear a PhD say something aanalagously stupid, give them a hug from me.

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-the good reverend drone

 
rev drone
Member   posted 10-26-1999 07:41 PM          
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Yes, I don't believe there's anybody contending that NaBH4 won't reduce an imine to an amine, but there's still this issue of chemoselectivity here. Look at the yields people are reporting with the alledgedly inferior reagent. As for simplicity, again NaBH4 wins out; sure adding NaBH4 by the quarter teaspoon is a drudgery, but compare that to testing and retesting the pH of a NaCNBH3-based reduction for hours on end. With all this going for it, still people put forward NaCNBH3 as being the most desirable choice in this matter.
I hate to be cynical, but I'm starting to agree with Osmium. It really looks like its a matter of ignorance and laziness.

When a grad student gets their PhD, they are covertly injected with a sophisticated neurotoxin during the graduation ceremony, which destroys the part of the brain that enables a normal person to say things like "I don't know", and "I'm not sure." The result is, when pinned to give an answer, they automatically will grasp at anything to cover up their infermity. "Well, yeah. Sodium cyanoborohydride is CLEARLY superior to sodium borohydride for reducing imines; every IDIOT knows that..." Sad, sad, sad. Next time you hear a PhD say something aanalagously stupid, give them a hug from me. They need to know we understand their plight, and its okay.

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-the good reverend drone

 
Park, Inc.), 1998 - 1999.