[Nekromantis]

Hi, I have a big problem. In my research I need to join pyrrolidine, piperidine or morpholine to many cyclohexyl alcohols. But it’s a little problem – How?. I transformed –OH group to Cl, and I tried PTC reaction with Na2CO3 or NaOH in toluene, benzene and like a catalyst I used tetra-n-butylammonium hydrogen sulfate. But this reaction failed. I would try with p-Toluenesulfonyl chloride. And now is question for you. How to brake away –OTs and join my cyclic amine? Maybe reaction with sodium? NaOH ?

Sorry, for my english

[sjb]

+ e.g. to ? How did it fail, what did you get back? I'd think about reductive animation, perhaps; or some of the hydrogen borrowing reactions by Williams et al (amongst others)

[Nekromantis]

NMR analysis showed mixture of alcohol and amine.

[sjb]

What about other methods? TLC for instance. I can't see NMR by itself being that diagnostic as the majority of your change is with exchangeable protons anyway.

[Dan]

NMR analysis showed mixture of alcohol and amine.

Which amine - tert amine product or secondary amine starting material?

If you see cyclohexanol in the mixture, that indicates competitive (or preferential) hydrolysis. Performing the reaction under anhydrous conditions should prevent it.

As has been suggested, reductive amination is usually the preferred method for this type of transformation.

[Nekromantis]

NMR analysis showed mixture of alcohol and amine.

Which amine - tert amine product or secondary amine starting material?

If you see cyclohexanol in the mixture, that indicates competitive (or preferential) hydrolysis. Performing the reaction under anhydrous conditions should prevent it.

As has been suggested, reductive amination is usually the preferred method for this type of transformation.

NMR showed alcohol and secondary amine - pyrrolidine or piperidine... i thought about amination but catalysts using in this reaction are very expensive and i dont have guarantee that this reaction will be positive.

[orgopete]

If the products are known compounds, you could check to see how they have been prepared in the literature.

[Dan]

catalysts using in this reaction are very expensive and i dont have guarantee that this reaction will be positive.

10% Pd/C is not so expensive, 1 g is cheap enough to buy for a test even if you are worried it won't work, certainly cheaper than spending your time running lots of reactions with 0% yield.

[Nekromantis]

catalysts using in this reaction are very expensive and i dont have guarantee that this reaction will be positive.

10% Pd/C is not so expensive, 1 g is cheap enough to buy for a test even if you are worried it won't work, certainly cheaper than spending your time running lots of reactions with 0% yield.

1g cost about 30$ but I need 50-100 g final compound to make all physicochemistry and reactions.
Maybe Grignard reaction between cycliccompound-MgBr and amine? Convert -OH to Cl eg. SO2Cl, next step reaction with Mg and finaly with pyrrolidine?

[Dan]

1g cost about 30$ but I need 50-100 g final compound to make all physicochemistry and reactions.

Yes, but it shortens your synthesis to 1 step and the reaction is usually so clean that very minimal if any purification is necessary. I appreciate that Pd/C is not the cheapest reagent in the world, but if you cost all the reagents and labour time required for a messy alcohol activation/S_N2 procedure, you might be surprised.

Maybe Grignard reaction between cycliccompound-MgBr and amine?

What is the mechanism for that transformation?

[Nekromantis]

1g cost about 30$ but I need 50-100 g final compound to make all physicochemistry and reactions.

Yes, but it shortens your synthesis to 1 step and the reaction is usually so clean that very minimal if any purification is necessary. I appreciate that Pd/C is not the cheapest reagent in the world, but if you cost all the reagents and labour time required for a messy alcohol activation/S_N2 procedure, you might be surprised.

Could you give me a some leads for article where its using Pd/Cl ?

Maybe Grignard reaction between cycliccompound-MgBr and amine?

What is the mechanism for that transformation?
[/quote]

I read, that this reactions fail. I thought that, MgBr could react with N atom in amine... I have (-)-menthol and I transformed -OH gropu to Cl, but reaction between this Cl and amine dont work... Why? I did many PTC reaction, N-alkilation and result was great. But in menthol don't want react.

[Dan]

Could you give me a some leads for article where its using Pd/Cl ?

I had a quick look and actually it seems catalytic reductive amination of cyclohexanone with secondary amines and H₂ is much more challenging than I thought - it is usually performed at high temp and pressure, so maybe not suitable for you. Sorry about that. There are lots of other methods though, see here for leads:

http://www.organic-chemistry.org/synthesis/C1N/amines/reductiveamination.shtm

[Doc Oc]

Cl is a very bad leaving group. Better options would be to convert it to a Br or I, or more simply to mesylate or tosylate the alcohol (which you suggested the the p-TsCl). Dissolve that in DMF, add some K2CO3 and the amine. Heat may be necessary to facilitate reaction, but I've done lots of amine alkylations this way. Cl has never worked, I've always needed to swap it for a more labile leaving group.

[AWK]

http://dergipark.ulakbim.gov.tr/tbtkchem/article/viewFile/5000024385/5000024622

[kriggy]

 Reductive amination is usualy done with borohydride reagents which is rather expensive but you can get 2kg bottle from sigma at some 1500$. Also, you might get discount or find cheaper, however, there are many borohydride regents and some might work and some might not but I think your molecules seem simple enough that NaBH4 will be fine. Also, you might try it with Hantzsch ester like D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter, S. Rudolph, Org. Lett., 2006, 8, 741-744. You could make it in kilo amounts because the synthesis is well described (we do it in undergrad labs you might get your students involved too if you find good procedure/ purification method.

And of course, then there is the famous Buchwald-Hartwig or Chan-Lam (If you can get the boronic acid easily)