Sciencemadness Discussion Board

Reduction of 2-Piperidone (delta-Valerolactam)

Sauron - 18-4-2007 at 02:05

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.

sonogashira - 18-4-2007 at 06:28

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.

not_important - 18-4-2007 at 08:03

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

garage chemist - 18-4-2007 at 09:27

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...

Sauron - 18-4-2007 at 09:37

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.

chemrox - 18-4-2007 at 23:47

the reason you're not using the Na/EtOH reduction is?

Sauron - 18-4-2007 at 23:58

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.

Nicodem - 19-4-2007 at 00:03

...'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.

Sauron - 19-4-2007 at 00:19

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]

chemrox - 19-4-2007 at 22:35

What is the borohydride/Br2 reax? Doesn't Br2 (by itself) halogenate the alpha position?

Sauron - 19-4-2007 at 22:47

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.

Nicodem - 19-4-2007 at 23:02

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]

Sauron - 20-4-2007 at 00:08

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]

60817.jpg - 23kB

Klute - 20-4-2007 at 03:21

F**king hell you got that beauty for 200$?! :o

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$?:D

Sauron - 20-4-2007 at 06:09

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.

evil_lurker - 20-4-2007 at 06:34

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.

Sauron - 20-4-2007 at 07:16

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]

evil_lurker - 20-4-2007 at 08:34

You suck arse Sauron. :P

You do realize this don't you?

Ok will stop post whoring and shut up now.

not_important - 20-4-2007 at 08:36

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.

Sauron - 20-4-2007 at 08:51

@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?

not_important - 20-4-2007 at 09:10

Quote:
Originally posted by Sauron
@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?


@#$%^&* 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 880 times

Sauron - 20-4-2007 at 09:45

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]

not_important - 20-4-2007 at 21:24

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.

Sauron - 21-4-2007 at 01:33

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.

not_important - 21-4-2007 at 08:16

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.

Sauron - 21-4-2007 at 08:53

QSAR/QSPR is not so much a matter of theory as it is the assembly of empirical datasets and then the application of advanced statistical methodology and a lot of silicon (but definitely still desktop) to fill in some gaps.

I recommend CODESSA from Semichem (Andy Holder at UM) with a AMPAC 8 front end although you can also go with a Gaussian 98W front end or MOPAC if you prefer. Just don't mix results over different semiempirical (or ab initio) front end or you will be in GIGO hell.

Once you have an appropriate set of data to use to train your system you can accurately predict physical, chemical and biochemical properties for compounds that have not been made yet. The accuracy is quite similar to the error found in empirical data sets. For boiling points for example the sotware will give you a value +/- 8 C and the uncertainty in literature values is 7 C. This all works very well for bp's and related constants, GC retention factors, density, refractive index, octanol/water partitions, not so well for melting points yet.

The true cross is the so called inverse problem. Give the system the physical and chemical and/or biochem/pharm properties desired and let the system tell you all the molecular structures that will meet your wish list.

The inverse problem in QSPR remains unsolved.

stimo-roll - 2-5-2007 at 10:04

Maybe Wolff-Kishner Reduction with hydrazine hydrate and base will work? (JACS 68,2487,1946) or cycle can open?

[Edited on 2-5-2007 by stimo-roll]

dedalus - 2-5-2007 at 14:54

Quote:
Originally posted by Sauron
I
Someone posted in an old thread that Zn/HCl would do this jon. Others (particularly @Nicodem) were skeptical.

.


Don't you need the Zn to be amalgamated? I dimly recall this being called Clemmenson reduction.

Nicodem - 2-5-2007 at 22:55

It does not matter whether you amalgamate zinc or not since in neither case can you reduce amides or lactams (like I already said once in the other thread from where Sauron quoted that).
Quote:
Originally posted by stimo-roll
Maybe Wolff-Kishner Reduction with hydrazine hydrate and base will work? (JACS 68,2487,1946) or cycle can open?

The Wolff-Kishner reduction only works on certain ketones and aldehydes so how could it be relevant for the reduction of delta-valerolactam? The reference you cited certainly contains no amides as substrates.

dedalus - 3-5-2007 at 07:57

To think I once fancied myself an organic chemist.

That was back some time around the Norman Conquest, I also dimly recall.:D