I would suggest (as others did) to first mono-protect the diamine with Boc (or a different protective group). The unchanged piperazine, the mono-Boc- and the di-Boc-derivatives of diamines are usually easily separated.

For the alkylation I would propose to use reductive amination (treatment with butylaldehyde and a reducing agent such as NaBH3(CN) or NaBH(OAc)3) rather than nucleophilic substitution with butyl iodide. By reductive amination, no quarternary ammonium salts can be formed.

Desculpe a ousadia mas por acaso já viu este método : http://www.orgsyn.org/orgsyn/prep.asp?rxntypeid=21&prep=CV5P0088

All the best and good luck

Try to protect one of the amino groups

I have mono-protected diamines and triamines with Boc anhydride (0.5 equiv). The amine was dissolved in dry DCM (1.13 M solution). Then, a solution of Boc anhydride (1.13 M) in dry DCM was added dropwise over 2h. The resulting suspension was stirred 3 h, filtered and the solids werw washed with DCM. The resulting solution was concentrated in vacuo to give the product as a colourless oil.

To remove the Boc group with dioxane / HCl 4 M solution commercially available

WE have made the reaction, with different alkyl halides many times. The best way is to use BOC piperazine, with one of the nitrogengs blocked, and making the alkylation in the other nitrogen, using a base -potassium carbonate on acetonitrile, or EDIPA on ethyl acetate or acetone- in our experience, monoalkylation of piperazine, without protecting group is never a clean reaction. Alt the end, you can simply reflux the mixture of isolate the product and trieating it in the presence of an acid, to obtain the monoalkylated piperazine.

If the solid went to the aqueous layer, it is probably because it is in the protonated form. Try to neutralize your aqueous layer with some sodium carbonate solution, hopefully this will bring the product to the organic layer.

check this reference by Gao, Feng-Li et al; Bioorganic & Medicinal Chemistry Letters, 13(9), 1535-1537; 2003 might be useful. They protect one of the NH of piperazine and then alkylate the free NH, followed by hydrolysis of the protected NH.

Dear Dr. Americo, I've tried this method, but the result was the one that I described in the question. Thank you for the suggestion!

Dear Dr. Zader, I've done it before too, but only a quite small ammount of the product went back to the organic layer.

All attempts made till now appear to work, but I think my problem is during the workup. The product seems to be formed, but it remains in aqueous layer. I've evaporate the aqueous layer, and then extracted the organic compounds from the solid formed using EtOH, however, the yellow solid obtained from this procedure (probably a mixture containing piperazine and the product) is not soluble in other organic solvents, such Et2O or AcOEt... It makes sense for anyone?

The easy way is to use BOC piperazine, and make the alkylation in the other nitrogen, using a base -potassium carbonate on acetone. you can reflux the mixture of isolate the product and trieating it in the presence of an acid, to obtain the monoalkylated piperazine. Eur. J. Org. Chem. 2001, 2825-2839.

1-Boc-piperazine: A solution of Boc2O (4.37 g, 20.0 mmol) in DCM (50 mL) was added over a period of three hours to a solution of piperazine (3.44 g, 39.9 mmol) in DCM (100 mL). The mixture was allowed to stir for 22 hours before the solvent was evaporated. Water (100 mL) was added to the residue and the insoluble product was removed by filtration. The aqueous solution was extracted with DCM (three portions of 100 mL) and the combined organic layers were evaporated to afford Boc-piperazine (3.08 g, 83%).

Deprotection of Boc: TFA (10 mL) was added at 0 C to a solution of 1-Boc-piperazines (12.9 mmol) in DCM (30 mL). The mixture was stirred for 30 minutes at room temperature and then concentrated in vacuo. NaOH (1 M, 150 mL) was added to the residue and the aqueous layer was extracted with DCM (150 mL and subsequently 100 mL) and the combined organic layers were dried with MgSO4 and evaporated to afford monosubstituted-piperazines (high yields)

Continuous flow ! I am very involved in continuous flow chemistry. It is the easiest way for this kind of reactions.

Monoalkylation of piperazine without a protecting group will never give a clean product. If you think that there is possibility of piperizine in the yellow product, then why dont you vary the reactants. Do vary the ratio of the reactant and the reagent and see whether it will be solved or not.

I would suggest (as others did) to first mono-protect the diamine with Boc (or a different protective group). The unchanged piperazine, the mono-Boc- and the di-Boc-derivatives of diamines are usually easily separated.

For the alkylation I would propose to use reductive amination (treatment with butylaldehyde and a reducing agent such as NaBH3(CN) or NaBH(OAc)3) rather than nucleophilic substitution with butyl iodide. By reductive amination, no quarternary ammonium salts can be formed.

I hope the following patent may help you if you prefer change in reagent.

http://www.google.com/patents/US3948900

Dear Joao Paulo dos Santos Fernandes,

Concerning your reaction for the monoalkylation of piperazine, I think you have more than one option you can consider.

In the first option, perhaps the most immediate and brutal, you can try the direct monoalkylation of piperazine by reacting

Piperazine (1.0 eq.)

AcOH (0.5 eq.)

MeI (0.4 ÷ 0.45 eq.)

Solvent - trifluoroethanol, at low temperature (5 ÷ 10 °C).

In the second option the entire process is a bit longer, but surely more effective. It consists in blocking one of the nitrogen atoms, and reacts the mono-blocked piperazine derivate with MeI. In order of obtain this intermediate, you can use a blocking-group like Fmoc-Cl (0.5 eq.). After separation of mono- and bi-Fmoc protect piperazines, you can perform alkilation using the monoderivate, a strong excess of MeI, and an aromatic base, as scavenger for H+.

I hope this information has been helpful to you.

Dear Joao Paulo,

You might be facing problems with double alkylation on the same nitrogen leading to quaternary salt formation, reason why your product is so water soluble. Stefan hit the nail on the head: use Boc-protected piperazine to direct alkylation only to one nitrogen, and then do reductive amination (or use any variant of the the Escheweiler-Clark reaction). Finally, remove the Boc-protecting group. Good luck!

Dear use BOC piperazine,

1-Boc-piperazine: A solution of Boc2O (4.37 g, 20.0 mmol) in DCM (50 mL) was added over a period of three hours to a solution of piperazine (3.44 g, 39.9 mmol) in DCM (100 mL). The mixture was allowed to stir for 22 hours before the solvent was evaporated. Water (100 mL) was added to the residue and the insoluble product was removed by filtration. The aqueous solution was extracted with DCM (three portions of 100 mL) and the combined organic layers were evaporated to afford Boc-piperazine (3.08 g, 83%).

Deprotection of Boc: TFA (10 mL) was added at 0 C to a solution of 1-Boc-piperazines (12.9 mmol) in DCM (30 mL). The mixture was stirred for 30 minutes at room temperature and then concentrated in vacuo. NaOH (1 M, 150 mL) was added to the residue and the aqueous layer was extracted with DCM (150 mL and subsequently 100 mL) and the combined organic layers were dried with MgSO4 and evaporated to afford monosubstituted-piperazines (high yields)

Dear Dr. Joao Paulo dos Santos Fernandes,

Undoubtedly, the method offered by most experts, consisting in a preliminary protection of NH-piperazine moiety is the best. However, to save time and do not perform more stages, you can use a more simple way for monoalkylation. One consists of in the heating of an excess of piperazine with alkyl halide in a large quantity of liquid base, usually pyridine.

For example, 100 mmol piperazine were mixed with 25 mmol of the alkylating reagent in 30 ml of pyridine. Contents refluxed for 12 hours. After cooling to room temperature, the reaction mixture was placed in a freezer at night. The residue consisting of excess piperazine and the corresponding pyridinium salt was filtered off and washed with acetone. The filtrates were combined and the solvents removed on a rotary evaporator. The residue was heated in vacuum line (20 mm Hg) at 80-90°C for several hours (to remove traces of pyridine) and then subjected to fractional distillation. Usually, monoalkylated piperazines have a boiling point between 100 - 150 C (20 mm Hg). Dialkylated derivatives in these conditions are not distilled. Typical yields for monoalkylpiperazines ~ 70-80%.

Hi,

I see all methods described here quite feasible and helpful, but I would stick to the last one which by all means would save you time and more importaly for an organic chemist maybe some column chromatographies. I would use a large excess of piperazine and also quite dilute solution combined with a slow addition (dropwise) of the alkylating agent. I did alkylation on BINOL under reflux using K2CO3 in acetone so I guess similar conditions would apply to you. Bear in mind that I wanted double alkylation, hence large excess of diluted diamine should help too.

If you think the problem is the work-up...with and acid-base extraction should be no problem, but i guess you've tried that too, no?

Good luck!

I think the diakylation of the same nitrogen atom on the sustrate giving quatenary products is one of your problems dear, as suggested by others. I would want to go with suggestion on reductive deamination.

The best method for N-monosubstitution on piperazine is described in patent CZ 2011/0847 (A3), Pazdera P. et al.

Mixture containing 1 eq piperazine (anhydrous), 1 eq. piperazine dihydrochloride and methanol is heated to a solution formation. This solution contains piperazine monohydrochloride in situ (Attention! The solid piperazine is back formed after cooling of this solution and its will be the least soluble compound in reaction mixture after reaction, as well!). Monoprotonated piperazine is protected against N, N´-disubstitution reaction, however, its nucleophility is lower than the one of the free piperazine (compare pKa values for mono- and bisprotonated piperazine: 5.40 and 9.61, respectively). Therefore, it is necessary to activated alkylating agent, i. e. alkyl iodide, by action of transition metal ion such as Cu(I), Cu(II), Fe(II), Fe(III), Ag(I) or their mixture (e. g. Cu(II)-Ag(I)), supported on weak acid cation-exchanger of a polyacrylate macroporous kind, ideally. Preparations and synthetic application of such supported catalysts are described in patent CZ 2011/0799 (A3), Pazdera P. et al.

Now, the alkyl iodide (1 eq) is added dropwise into the hot/boiling piperazine monohydrochloride solution (see above) containing a supported catalyst. Course of the reaction is monitored by TLC on silica-plates, eluent is methanol, detection of spots by ninhydrine agent, presence of alkyl iodide in vapors above the reaction solution by paper saturated with AgNO3. After end of reaction the solid catalyst is filtered off, reaction mixture is cooled and main part of solid piperazine dihydrochloride is precipitated. The residual piperazine dihydrochloride is precipitated by an addition of a small amount of isopropyl alcohol. The residual solution containing 1-alkylpiperazin-4-ium iodide is evaporated and crude product is recrystallized from isopropyl alcohol or from mixture EtOH-iPrOH. Yield more than 60 %.

If the free base of your amine is soluble in a relatively no polar solvent (ether or hexane are best, but dichloromethane will work) then you can dissolve the amine in the solvent. Add the alkylating agent (neat or in the same solvent) dropwise, slowly. Be sure and have excess amine.

The initial monoalkylated product formed is a salt - insoluble in the nonpolar solvent - it precipitates. Filtration gives the product as a solid. You can dissolve in water, add base, and extract if you need the free base.

This method is quick but it does not work in all cases.

As previous contributors suggested, the best way would be use the monoBoc piperazine in a slight excess to avoid quaternarisation. I guess it will allow you to use milder reaction conditions, especially, if your iodide is slightly unstable. That is if your final product is stable in strong acidic conditions, if not, of course, use another compatible (for your molecule stability) protecting group.

Another much less subtle approach, I used in the past, is to repeat your reaction with a larger excess of piperazine to favorise mono-alkylation over the by-products and then add Boc anhydride (at such a stoechiometry to protect all the free NH). After extraction, run a careful chromatography.

Use N-formyl Piperazine ( available commercially too) , make alkylation and then hydrolysis by basic medium will give Mono-alkylated piperazine.

The product is being produced as a double salt (HCl and HI), so the water solubility is hardly surprising. Evaporate the ethanol, dissolve in water, adjust the pH to where the free base is present (about pH 9.5 for piperazines), and extract with the least polar solvent that dissolves your product. (My first candidate would be toluene.) Back-washing with bicarbonate should remove residual piperazine.

When piperzine is refluxed with acetic acid, the reaction will endup with 75:25% of mono:diacetyl piperizine. This is one of the economic way of making monoacetylated piperizine. then you can do the alkylation forllowed by deprotection of acetyl group.

May be after deprotection you can separate piperzine from your mono alkylated piperizine

I suggest you add the alkyl iodide to 2-3 excess equivalent piperazine (as a free base) in ethanol and reflux. Monitor consumption of the iodide by TLC. When the iodide has been consumed, remove ethanol under reduced pressure. Partition the crude material between water and methylene chloride. Extract the aqueous layer with methylene chloride, dry the combined organic layer (Na2SO4) and remove solvent under reduced pressure. 1H NMR analysis of crude material will indicate purity of alkylated piperazine, which can r be used in the next step without further purification. You can also purify by column chromatography on silica gel (7-10% MeOH in dichloromethane). This is a more convenient method, compared to the 2-step Boc protected piperazine.

What do you mean, "obtain it from the aqueous solution without extracting it?"

I think that is what you should do. I believe you have the TM in solution as the N1 ethyl-N2-piperazineHCl in water. Treat the solution with K2CO3 until basic and extract with ether or dcm. I'm cheap. If I can avoid running to BOC cmpds I will. The mono HCl provided the protection you needed as it was.

Dear Nicholas, I would like to say to obtain the alkylated product from aqueous layer without any non-substituted piperazine. Obviously, I tried the basic extraction with K2CO3, but the "yellow coloured" product in aqueous layer don't come to the organic phase. The organic layer remains "clean", and this can be seen after evaporation, where no product is obtained (in fact, nothing is obtained!).

I prefer to use the piperazine monoHCl approach too, mainly because the cheapness.

OK- I'm sorry I though maybe there was an easy out. Do you suppose you've generated a quaternary salt? Sometimes these can be avoided by careful manipulation of the reagent concentrations but usually a lot of frustration is the result. I would try this again using piperazine dihydrochloride with an equivalent of alkylchloride and a stream of dry HCl until white needles precipitate. . Please let me know. I have a similar problem. Also I think benzyl piperazine is cheaper than BOC and as easy to de-couple...

Just so you're aware, benzyl piperazine is a controlled substance (drug of abuse). I was surprised to learn this a few years ago when looking for monoprotected piperazine derivatives.

The best way is flow chemistry. You add together the stoichiometry of 1 for 1 in a continuous flow. Two pumps, some pipes, and a static mixer. Total selectivity !