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Sauron
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Reduction of 2-Piperidone (delta-Valerolactam)
I want to prepare this lactam then reduce it to piperidine.
Someone posted in an old thread that Zn/HCl would do this jon. Others (particularly @Nicodem) were skeptical.
So how to do this?
Making the lactam is easy. Cyclopentanone, commercial or prepared from adipic acid, is subjected to Beckmann rearrangement of its ketoxime, a slow but
mild procedure using TCT/DMF adduct and DMF as solvent.
I need some piperidine for Fmoc peptide work, for which a dil soln is standard deprotection reagent.
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sonogashira
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LiAlH4 will do the job with a 44% yield, see here
(sadly i don't have access to this journal)
BH3-THF would likely proceed fairly well. I've never heard of reducing an amide with a modified clemmensen reduction though.
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not_important
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A variant on BH3 is borohydride plus BF3.ether, for in situ generation of BH3.
But I can't find anything in my notes that resembles sing Zn/HCl. There is this
| Quote: | The reaction of Vilsmeier complexes of primary, secondary and tertiary amides with zinc-ethanol affords the corresponding amines in high yields.
A new method for the reduction of amides with zinc-ethanol
Journal Cellular and Molecular Life Sciences (CMLS)
Publisher Birkhäuser Basel
ISSN 1420-682X (Print) 1420-9071 (Online)
Subject Biomedical and Life Sciences
Issue Volume 33, Number 1 / January, 1977
Category Pro Experimentis
DOI 10.1007/BF01936778
Pages 101-102 |
This not too high pressure catalytic method sounds interesting, but it is from patent-land
http://www.wipo.int/pctdb/en/wo.jsp?WO=2005/066112
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garage chemist
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If piperidine is your desired product, I'd recommend looking into the cathodic reduction of pyridine, which is extremely simple and involves no
chemicals other than sulfuric acid, lead electrodes, and NaOH for freebasing the piperidine and maybe an extraction solvent.
I remember a patent or something I have read that made me realize how simple it is to make piperidine from pyridine.
Don't know which one it is at the moment...
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Sauron
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It is also dead simple to reduce pyridine with Na metal in ethanol, and I have a whole lot of Na metal. 6 Kg)
But I was hoping to exploit this cyclopentanone -> valerolactam -> piperidine route. I am not inclined to use my precious Kg of LAH in this
fashion particularly not for a 44% yld.
The electrochem route is probably simplest. But I have never much cared for such. Just not my preference. My old boss was a big electrochem type, but
given the choice when I joined him I went with his other interests not that one. He was big on bimolecular reductions, like acetophenone pinacols.
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chemrox
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the reason you're not using the Na/EtOH reduction is?
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Sauron
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Because I find the route from cyclopentanone (itself preparable from adipic acid) via TCT/DMF very appealing.
Also pyridine stinks.
The method hinges on whether or not a facile way to get from 2-piperidone to piperidine can be found.
LAH is too precious. Borohydride/Br2 maybe, but I am still hoping for something even simpler/cheaper.
Or else, pyridine it is.
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Nicodem
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...'cause Na in alcohols reduces amides to the appropriate alcohols (in this case 5-aminopentanol) and the amines (piperidine) which is usually only
the minor product. In the case of lactams there might be more of the desired product, but I would not put a bet on it unless I see experimental data
demonstrating it.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Sauron
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Sorry if I was not clear, I was NOT proposing Na/EtOH redn of the lactam, but of pyridine, which is well known and classical.
Trying to establish a simple reduction of the lactam is what this thread is about. Someone suggested I just chuck the idea and fall back on
Pyr/Na/EtOH.
Hence your misreading.
-----------
Someone asked why I don't want to reduce pyridine with Na metal
To reduce 130 g Pyridine takes 450 g Na metal. So already this is ridiculous on its face. To reduce a liter of pyridine would take 3600 g Na. 8 lbs.
I own 12 lbs. I do not want to waste it like this.
Furthermore the reduction produces vast amounts of sodium ethoxide which must be hydrolyzed with water and the piperidine isolated. What a mess.
Maybe @GC's electrochem suggestion is worth a look.
[Edited on 19-4-2007 by Sauron]
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chemrox
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What is the borohydride/Br2 reax? Doesn't Br2 (by itself) halogenate the alpha position?
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Sauron
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I think we've been over all that in another thread. 2- bromopiperidine does not exist. It eliminates to form a pi bond. I assume the NaBH4 reduces
that.
Anyway Br2 is also dear.
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Nicodem
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| Quote: | Originally posted by chemrox
What is the borohydride/Br2 reax? Doesn't Br2 (by itself) halogenate the alpha position? |
The alpha position of what? Of piperidin-2-one, piperidine, pyridine or what now?
Bromine N-brominates amides in the presence of HBr scavangers to form N-bromoamides. Similarly it N-brominates piperidine to form 1-bromopiperidine.
Since the only position in pyridine that is nucleophilic is the position 1, bromine reacts only with it forming N-bromopyridinium bromide (C5H5N*Br2).
In no case does it react with any alpha position.
1 eq. of bromine and 2 eq. of sodium borohydride give the expected redox reaction:
2NaBH4 + Br2 -> 2NaBr + H2 + B2H6
[Edited on by Nicodem]
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Sauron
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Thanks @Nicodem
Got any suggestions for redn of 2-piperidone other than LAH or NaBH4/Br2?
I just bought a Parr 4560 series mini-reactor with a working cap. 400 ml, heated and stirred, pMax 3000 psi. This one is SS 316 but they have
interchangeable vessels in Hastalloy C, C-2000, Inconel, Carpenter-20, Ti, Zirconium, etc. if you can stand the price. So catalytic hydrogenation is
on the table (or bench) and no longer limited to my glass vessel shaker apparatus from same vendor which only goes to 75 psi/80 C anyway.
Got this thing for $200, with stand, motor, and heater. As this is a $20,000 item new I am pleased and will have fun with it. The gauge on it now is
600 psi but vessel is rated to 3000 psi and I can change gauge out. The reactor itself is 2.5" diameter while that shell around it is heating mantle.
Stirring is normally mag coupled impeller but can be changed to packed gland shaft drive for higher torque when stirring viscous mixtures. This
reduces Pmax to 2000 psi.
The unit uses a controller that runs both heater and stirrer and has options for pressure display and temp display for remote monitoring and data
logging I suppose. It's a pretty nice and versatile little setup.
[Edited on 20-4-2007 by Sauron]
[Edited on 20-4-2007 by Sauron]
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Klute
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F**king hell you got that beauty for 200$?! 
Can't you just reduce pyridine with it? You won't smell it sealed at those pressures!
would you sell it to me for... 250$?
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Sauron
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I got it as a new arrival at a large outfit that I buy a lot from, and sometimes they just mess up and underprice. In this case the control box is
missing (which runs the mirit and the mantle) and I will have to source that seperately. But another dealer I also buy from has same unit as this,
also sand controller, and wants $10,000. Go figure.
By the time this 70 lb beast is shipped to W.Coast then freighted across the Pacific I will have several multiples of the selling price in it, and
still have to find a controller. No doubt there are alternatives. The mantle is very likely a Glas Col OEM and so can be replaced by a Glas Col 220V
mantle and controller. That only leaves the stirrer motor to sort out, also replaceable to 220 V and so what does that leave? The thermocouple, just
run it to a digital thermometer that is selectable type J/K/T. Piece of cake. I have two. And an extension cord. So maybe I can do without the
dedicated Parr controller at least till one comes along for cheap.
The costliest item will probably be a new reaction vessel if I decide to buy one from Parr. Can't tell which size this one is, they come in 160, 300,
450 and 600 ml and the working capacities are 2/3 of that. I will want a 6oo ml one and probably, something more chemically inert than SS 316.
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evil_lurker
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Sauron I think you have me beat by a long shot, but I've still gotten a few good deals.
Recent additions this week are a 500ml Pyrex was bottle for $30 and a Savant RT100A refrigerated condensation trap for $152 (similar units in similar
condition usually run around $1000, brand new around $2600)... fired it up with about 700ml of methanol and she dropped the temp down to around -25 in
30 minutes... its probably at least 10 years old and may need some gas put in it for max efficiancy.
Past additions were matheson corrosive gas regulators... one for chlorine and one for hydrogen acids... CGA 330 and CGA 660 fittings.... picked up
both of them for less than $200 (figure they were worth new $800 and $1200 each)
A J-Chem digital vacuum regulator, for $250 ($1200 new)
If ya know what your looking for, you can have some damn hi tech shit for pennies on the dollar.
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Sauron
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Yeah sometimes the dealers just figure it wrong.
Other times you see stuff priced close to new retail, go figure.
That Bryant trap sounds nice.
The Parr things do tend to be money pits by the time you get them completed with whistles and bells. That was my experience with the 3911 shaker
hydrogenator.
To answer Klute's question, yes, catalytic hydrogenation of pyridine is not too demanding. 5% Pd/C is typical, and 100 psi/90 C will do the job at
least for some of the substituted pyridines. That is just beyond reach of the Parr shaker, which is officially rated at 60 psi but is actually capable
of 100 to 150, if you want to push things. They test their bottles at 125.
But this steel vessel is rated at 3000 psi so 100 is a walk in the park.
Turns out it is a 4521 Model not 4560 series, the difference is this is 1 Liter. Can be reconfigured to 2 Liter. No complains from
me!
[Edited on 20-4-2007 by Sauron]
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evil_lurker
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You suck arse Sauron. 
You do realize this don't you?
Ok will stop post whoring and shut up now.
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not_important
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Sauron, with that toy you may want to look at that wipo reference I mentions, claim is reduction of amides in decent yields at 10 to 15 bars and less
that 150 C.
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Sauron
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@n_i, I just tried the link you gave me, it gave me an error message
http://www.wipo.int/pctdb/en/wo.jsp?WO=2005/066112
Can you get the patent and post it here?
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not_important
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@#$%^&* Europeans - it's t he '/' in the URL parameter. Here's the document
[Edited on 20-4-2007 by not_important]
Attachment: Method_for_Catalytic_Reduction_of_Amides.pdf (1.2MB)
This file has been downloaded 816 times
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Sauron
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Interesting but no literature citations, no prior art citations, nothing to hang one's hat on.
----------------
Just got an email from the boss at the company selling me the reactor. Claims clerical error re price $199, was supposed to be $1999. Knocked it back
to $1499 for me, such a deal!
Well, it's still a good deal. Just not quite the complete steal it would have been at $199. Next cheapest one I can find is $3500, so I will still
take it.
[Edited on 21-4-2007 by Sauron]
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not_important
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Yeah, when I found that I did a little searching for related docs but found nothing close.
Notice that it is micro-reactor based research. I've seen a fair amount of combinatorial chemistry and micro-reactor stuff that is like that,
following the Thomas Edison school of invention - throw a bunch of stuff at the wall and see what sticks. A lot of this seems to hit as patents
before anything is published in a more scholarly fashion.
It looks fairly cheap to carry out, though, so it may be worth a try. I think one of the selections had no precious metals at still gave yields in the
40% range, 120 C and 10 bar of H2.
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Sauron
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I agree with your appraisal of combi-chem as a sort of scientific version of Jackson Pollock paintings. Splash some paint on a canvas, see if the
shape is interesting.
Remember what Nikola Tesla had to say about the hack, his former employer and later rival T.A.Edison: "Ninety percent of his labors could have been
replaced by a little thought and calculation."
And that is why I prefer computational chemistry to combinational chemistry. Without some thought and analysis on the front end, the more the better,
combi-chem is like putting 10,000 monkeys to work on typewriters and waiting for one of them to produce Shakesperean sonnets.
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not_important
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Well, the combi-chem is useful for going outside of the theories, empirical beats inferential.
And the thing about combi, microreactors, and all that, is that those monkeys are real small, and fairly quick, so you can pack a lot of them in the
back room to pound away until they hit something.
But, yes, thinking about the subject up front is important, as is being able to analyse the results in a meaningful way.
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