Sciencemadness Discussion Board - Cyclic Amines from Amino Alcohols

Cyclic Amines from Amino Alcohols

Steam - 15-9-2014 at 17:58

Ok, so I have been presented with an interesting problem in my class involving a Sn2 reaction. Say I want to form a cyclic amine of a certain length (doesn't really matter but for example I will say 5 carbons with 1 nitrogen). Would the following reactions work? Starting with 5-Aminopentanol, tosyl chloride is added to the -OH group (I suppose Br or I could be substituted). This reaction, as I understand it, needs a strong H+ ion receiver (pyridine) in order for equilibrium to be driven to the product of the amino tosylate. Next the amine is protinated with a strong base? This is in order to remove the hydrogen. I also considered using Li or Na to possibility remove the amino hydrogen creating a nucleophillic amine. This nucleophile would immediately react internally with the tosylate leaving group producing a cyclic amine.

My questions are as follows.
1) Can a cyclic amine even from in this manner? Google searches did not reveal any help here.
2) If it could even happen, would polymerization product be the preferred outcome?
3) Is pyridine necessary as a solvent in the preparation of Sulfonate Esters? Could a simple base be used like NaOH or possibly an organic resin?
4) best way to turn NH2 into an NH- nucleophillic group?
5) *Probably the most important question* Is there a better way to do this???

[Edited on 16-9-2014 by Steam]

Texium - 15-9-2014 at 18:03

Quote: Originally posted by Steam

Not sure what you mean by that... Are you leaving something out?

Steam - 15-9-2014 at 18:20

Hahaha, perhaps zts16! *I accidentally* hit enter before I type the post! (Must be my over active trigger finger)

solo - 15-9-2014 at 18:45

.....maybe you´re trying to synthesise 4-piperidone.....solo

<a href="http://www.freeimagehosting.net/commercial-photography/"><img src="http://i.imgur.com/I21SzHr.png" alt="Commercial Photography"></a>

.....or its predecesor piperidone

<a href="http://www.freeimagehosting.net/commercial-photography/"><img src="http://i.imgur.com/i9TkSYz.png" alt="Commercial Photography"></a>

[Edited on 16-9-2014 by solo]

Brain&Force - 15-9-2014 at 19:47

Is this better visible? Any mistakes? I just gotta brag with my new tablet...

Crowfjord - 15-9-2014 at 20:42

@Steam, your scheme seems to me to be generally on the right track. As far as I know, tosylate is a good leaving group. Let me attempt to address your questions.

1.) I don't see why not, this is a pretty general reaction.

2.) Dimerization/polymerization would be a competing reaction. Dilution control would help in this case. The more solvent, the less likely it is for any given molecule to bump into another one before having a chance to react intramolecularly.

3.) AFAIK, pyridine need not be the solvent, but it or another non-nucleophilic base should be present to scavenge the acid formed from the substitution. Resin may work, as long as it isn't more nucleophilic than your intended nucleophile.

4.) Very strong bases are needed to deprotonate amines, but there is no need. Amines are already nucleophilic. The nucleophilicity can be modulated by choice of solvent (polar protic, polar aprotic, etc). Check your textbook or google SN2 reaction, and check out the links from .edu sites.

5.) Not sure

DJF90 - 15-9-2014 at 22:28

Everyone seems to be forgetting that amines are more nucleophilic than alcohols, and so the product in the first step will be predominantly the sulfonamide. You need to deprotonate the alcohol to shift the selectivity, and you won't be doing that with pyridine (pKaH =5.5, c.f. ROH ~18). My first attempt without a literature search would be Schotten Baumann chemistry, using aq. NaOH, BTEAC, and DCM (I've tosylated a polyethylene glycol monomethyl ether in quantitative yield (assay by 1H NMR) like this...).

As Crowfjord mentions, this material can polymerise and you may not be able to isolate it. The desired cyclisation is 6-exo-trig, meaning its "Baldwin allowed" and should proceed without issues (other than aforementioned polymerisation). Use of base for this stage may be detrimental, as the product is a stronger base than the starting material and will mop up the TsOH generated. This also protects the secondary amine from further Sn2 reaction. At the end of the reaction the amine can be free-based and isolated.

Steam - 16-9-2014 at 05:24

Quote: Originally posted by DJF90

Everyone seems to be forgetting that amines are more nucleophilic than alcohols.

Excellent point! This also would be problematic for any decent leaving group to replace the OH group... I am going to look into Schotten Baumann some more.

For the actual intermolecular SN2 reaction of the leaving group and the amine, my education tells me that a good polar aprotic solvent would be ideal. I am thinking acetone would be best or actonitrile? Also I would imagine this reaction would want to be kept at low temperatures to promote the intermolecular reaction.

plante1999 - 16-9-2014 at 06:19

Just trowing an idea here, but maybe protecting the amine with a protecting group, followed by adding the tosyl group on the alcool, and subsequently removing the protecting group could make the first desired compound.

Something I wonder, is it possible that pyrolisis of H2N(CH2)xOTs yield Toluenesulphonic acid and the desired amine, it appears to me the amine is much more volatile then the toluenesulphonic acid which may favour such a decomposition.

New problem

Steam - 16-9-2014 at 07:23

Ok so we got a secondary problem today. This problem is similar to the first but requires us to create a cyclic amino ether. I am not sure what this would be named. Maybe cyclo 1 ethyl amine ethyl ether? I am thinking that the best way to do this would be a dehydration reaction of alcohols? Or maybe somehow creating a Nucleophilic oxygen and reacting an an acidic medium? The problem I see with creating an alkoxide is first of all, preventing the dehydrogenation of the amine group, second preventing both alcohols from beinging oxidized.

Perhaps plante1999's suggestions about caping the amine with a protections group would be right. tert-butyloxycarbonyl protecting group maybe?

Also thanks for all the help everyone! These are very helpful comments!

DJF90 - 16-9-2014 at 07:50

Quote: Originally posted by Steam

Ok so we got a secondary problem today. This problem is similar to the first but requires us to create a cyclic amino ether. I am not sure what this would be named.

Its called morpholine. Theres a lab perparation using the acid route (not sure where I've seen it...).

Be careful you're not mixing up your terms. I see you've mentioned dehydrogenation but thats not correct; perhaps you mean deprotonation...

halogen - 16-9-2014 at 08:49

protecting group my foot

I believe what an ordinary person would do, boil the amine-alcohol in HBr, ammonium cation is its own protecting group in this situation. On neutralization, high dilution in a inert solvent favors cyclization over polymerization, at least to some extent.

Steam - 16-9-2014 at 09:57

Quote: Originally posted by DJF90

Quote: Originally posted by Steam

Ok so we got a secondary problem today. This problem is similar to the first but requires us to create a cyclic amino ether. I am not sure what this would be named.

Be careful you're not mixing up your terms. I see you've mentioned dehydrogenation but thats not correct; perhaps you mean deprotonation...

Yes sorry, I ment deprotonation. Don't want to take the electrons with it!

Steam - 16-9-2014 at 12:02

A little reasearch into morpholine showed that the ether oxygen can be formed from a double alcohol in the presence of a strong acid.

Screenshot_2014-09-16-15-01-20.png - 136kB

DJF90 - 16-9-2014 at 21:39

Thats what i said...

Analogously, you can make aziridine from ethanolamine. Theres a prep in Shirley's book, IIRC.

Steam - 17-9-2014 at 05:37

Thanks for the help guys! I appreciate it!

CuReUS - 19-9-2014 at 09:28

steam
i may be wrong but dont you think there should be a double bond in the middle of 5-amino pentanol for cyclisation to predominate over the polymerisation.

Steam - 20-9-2014 at 17:09

Yeah, I believe, as suggested to me, that by keeping concentration and heat low, polymerization will be kept to a minimum. If it was a problem, I would try that!

CuReUS - 21-9-2014 at 05:18

you could oxidise the alcohol to aldehyde using PCC and then do an intramolecular imine forming reactionby in the presence of acetic acid.finally you could reduce the imine to get the desired product