One thing we found mandatory for good tosylation yields was to recrystallize the tosyl chloride from hexane beforehand. A small, heavy layer always formed, containing highly-colored goods, particulates, and other undesirables. On small scale, just suck out the layer with a dropper; on large scale it's better to decant it, since the product will be trying to crystallize the whole time.

The yields were 85-90%, and the product emerged as beautiful colorless plates, very unlike the commercial product, and tosylation yields improved greatly and became reproducible.

Dear Rocardo, what reaction conditions are you using? A classic would be plain pyridine as solvent/base, with gentle heat... is a smalle group an option, mesylate would work well. Depends what you are trying to do I guess...

Hello.

The reaction conditions are simple: i've already try:

1) dcm with triethylamine / dcm with dmap

2) dry pyridine

3) acetonitrile

None of which worked. Any suggestions?

Thanks,

Ricardo

You could try a different base, like DMAP or imidazole. I could change DCM for DCE so you can heat to a higher bp.

You could try Amberlyst 15 for reaction hindered secondary alcohol

I feel it must be conducted in a pressure vessel (seal tube) using a strong base like DBU/NaOH. recently I read the reaction using potassium tert. butoxide

Even if you tosilate as some colleagues stated by the increase of reaction temp with DMAP/DMF etc. The following substitution reaction also be hindered and the conditions of substitution neccesarily should be for planar carbocation intermediary. So please first revise your complete synthetic strategy before you get into dead end strategies.

@Hiram

I wanto to perform a SN2 reaction, with a nucleophile entering through the alpha plane, which is significatively less hindered. However, and even in a SN1 reaction, several rearrangements can occur in order to form tertiary carbocation intermediates, which also are in positions less hindered.

Nonetheless, thank you for the suggestion.

Ricardo

CHEM. RES. CHINESE UNIVERSITIES 2010, 26(1), 55-59

Practical and Efficient Acylation and Tosylation of Sterically

Hindered Alcohols Catalyzed with l-Methylimidazole

Wu Qin- pei et al.,

Abstract Acylation of sterically hindered alcohols is frequent1y encountered in synthetic chemistry. An efficient and mild procedure for tosylation and esterification of sterically hindered hydroxyl groups with p-TsCl, AC20 and Bz20 in the presence of l-methyimidazole is described. It was observed that auxiliary base, triethylamine, accelerates the acylation reaction.

Try an Appel reaction (using CBr4 and O=PPh3 )instead of the Tosylation, the secondary alcohols can be more difficult to tosylate. Then its straightforward to add whatever nucleophile you want.

you can to use another protective group.For example TMS-CF3/TBAF. we use trifluoromethyltrimethylsilylation for protective stericaly hindered hydroxy-groups of steroids

Ok Ricardo i guess that by use of TsCl in NEt3 and acetonitrile during ca 30-40 min of MW irradiation should fastly provide your desired tosilated product. We have employed this strategy to tosilate polypropylenglycol in both positions thus primary as well as secondary positions reacted. Remove volatiles and add acetylacetate to precipitate ammonium salt and separate it from your product. Hope this helps.

Hiram

Why not Ms instead of Ts? MsCl is smaller and more reactive. However, above mentioned DMAP and microwaves are good suggestions in my eyes. If they fail, try a stronger base (DABCO -> tBuOK -> NaH). If you effectively generate the alcoholate, it would react.

I agree with Matej Babjak suggesting Mesylate and microwave. Pyridine, acetonitrile or dichloromethane as solvent. Trifluoromethanesulfonate could also work and give the best results: I found it the best leaving group for SN2 desplacement.

I would suggest mesylate or even triflate (Triflic anhydride is a lot more reactive). Depending on the nucleophile you plan to use, you could also consider a mitsunobu reaction (if the proton on the nucleophile is acidic). Another option would be to preform the alkoxide with a strong, irreversivble base like NaH or BuLi. Pyridine and TEA will typically often abstract the proton after addition occured rather than form an alkoxide (the equilibrium favors the alcohol and the base as neutral species, not charged ones, which is why NaH or BuLi could help).

Also, depending on the nucleophile you plan to use, it might be a good idea to go through the ketone instead of the alcohol as elimination will likely be a competing reaction with an hindered compound.

Finally, although the Apple reaction could be interresting (yielding the alkyl-bromide), keep in mind that this would give an inversion in stereochemistry. So overall, if you want the opposite stereochemistry than your starting alcohol, try through SN2 (Mitsunobu included). If you want retention, go through the Apple reaction (double inversion = retention). Hope it helps.

MsCl or Tf2O are excelent options. However in some cases the triflate derivative is too reactive and unstable (reacts with any nuclephile, especially with water during column chromatography). I recommend for Ts formation THF/water/NaOH or THF/water/KOH, for triflate formation distilled pyridine in dry dichloromethane is my elected choice.

I agree with Matej Babjak, DMAP in DMF is good as catalyst.

secondary alcohol is one in which the hydroxyl group is attached to acarbon atom which in turn, is connected to two carbon atoms, thus,tosylate an hindered secondary alcohol more diffcult reaction but occur this reaction in catalytic proton solvent for example [ DMF with drops conc H2SO4 and for uses THF/H2O/NaOH or Pyridine and TEA in order toobtained products with work analysis chemistry,,,,,,,,,,,,,,,,,,,,

Take diol in dichloro methane cool to -5 to 0°C, then add 1.9 mol.eq. triethyl amine then added 1.1 moleq. p-Tosyl chloride in dichloro methane, you will get selective secondary alcohol tosylate

it's very simple

Lapped in an Erlenmeyer flask equipped with a condenser and equipped with a magnetic stirrer,we dissolve 2.1g (53 mmol) of NaOH in 10 mL of water. To this mixture cooled to 0 ° C, 15 mmol of our reageant in 10 mL of THF was added dropwise. After 2 h of contact at 0 ° C, 6.29 g (33 mmol) of p-toluene sulfonyl chloride in 15 mL of THF was added dropwise. At the end of the addition, stirring was continued for 5 h at 0 ° C. The mixture is then poured into a cold solution of HCl (10%) and extracted with methylene chlorid (4x40 mL). The organic layer is washed with water (2x30 mL) and then with a solution of NaHCO3 (4x40 mL) and again with water (2x30 mL) until neutral pH. After drying over MgSO4 and evaporation of the solvent under reduced pressure, the resulting oil was purified by column chromatography

You can use HTIB (Koser's reagent) for for tosyloxylation by ligand exchange reaction.

I would go for MsCl before using Tf2O. If the triflate is the only option, I would recommend isolation of the crude material; NO purification attempts. Convert it directly with the nucleophile of choice.

Mitsunobu-conditions using DIAD, DPPA, PPh3 in THF is also worth trying...

All the best

Oliver

I have done mesylation of secondry alcohol in toluene at 0- -5 ° C. Take secondry alcohol in toluene at 0- -5 ° C and add 1.4 equivalent Triethyl amine stirred for 15 mints and add dropwise 1.2 equivalent methanesulphonyl chloride and stirred for 30 mints. at 0- -5 ° C.

I recommend you to use pyridine as solvent. Add TsCl (and a catalytic amount of DMAP, if necessary) and then heat the reaction mixture to 60~80 C. If these conditions fail to give the desired tosylate, try microwave irradiation conditions. However, mesylation would be much easier to bring about, as pointed out by the others. Good luck.

Mesylating the alcohol will work better. Add the methane sulfonyl chloride to the alcohol and add triethylamine dropwise at 0C. (the methane sulfonyl chloride will react with the Et3N to form sulfene CH2=SO2 which is much more active than the sulfonlyl chloride. An excess can be used also. After addition allow to warm to RT and stirr for an hour and work up.

Better reagent for peptide formation DCC,HOBT , Organic Base (Et3N) and Media MDC .

I suggest to use Ghrab Saad's method. It is simple and high yield. The purification is easier. Good luck!

Add iodide (KI. NaI), and perhaps 16-C-6; use HMPA as solvent, DMAP as promoter and DIPEA as base. Good luck!

I would recommend mesylation instead of tosylation

Try tosyl fluoride on the TMS ether:

V. Gembus, F. Marsais, V. Levacher, Synlett, 2008, 1463-1466.

They report 95% yield, on a quite hindered secondary alcohol.

If that fails, I'd throw TsF at the alkoxide, in DMSO.

Try dissolving your alcohol in anhydrous DMF, add Ts2O, cool the reaction mixture to 0 degree C then slowly add NaH.

I've had luck using triethylamine as base in dichloromethane, start the reaction cold and warm to room temp. All the solvents must be dry or your TsCl will not survive to tosylate your alcohol. Add the TsCl as a solid or solution slowly to the stirring solution of the substrate.

One thing we found mandatory for good tosylation yields was to recrystallize the tosyl chloride from hexane beforehand. A small, heavy layer always formed, containing highly-colored goods, particulates, and other undesirables. On small scale, just suck out the layer with a dropper; on large scale it's better to decant it, since the product will be trying to crystallize the whole time.

The yields were 85-90%, and the product emerged as beautiful colorless plates, very unlike the commercial product, and tosylation yields improved greatly and became reproducible.

Use the Hanessian's trick: imidazoles sulfonate in place of Tos. Tetrahedron 1996, 10557. Usually that works better.

The attached publication may help you

Procedure:

1 eq. of Alcohol+ 2.5 eq. of MOM chloride + 3 eq. of K2CO3 in Dry acetone keep it at 0 degree for 2 hr and than left it for 24 hr it may work

try DMF/THF 4/1, with 5 fold excess of K2CO3, at 50-60 degrees, for 2 days

Considering that your molecule is sterically hindered, I would recommend that you consider esterifying with MsCl instead of a Tosyl (in THF and 1.2 eqv Et3N). but the problem with a MsCl is you will be limited with the amount of a base equivalence (usually does not tolerate beyond 1.5 eqv of nucleophilic bases). you will often find it pretty tricky with hindered alcohols to drive the reaction when using a tosyl in which case about 3 eqv of Et3N or 1.5 eqv KOH pellets in THF works perfect for a tosyl). Again I almost find it slow in DCM though its the most cited solvent in the literature. ...good luck!

HIndered secondary alcohols can be very difficult to tosylate. I would advice mesylation or halogenation instead.

Good first need to have an alcohol!

If the problems is stereo?

OK! two things can solve alone or added

First you can use MsCI to reduce steric hindrance (Ts and Ms are the same thing) then you can reduce the volume of solvent to approach peers and third can heat the mixture a bit!

I think this solves!

@Mr. Ghrab Saad; please give us the details on the chromatography. Solid phase was silica, alumina? what mesh? what solvents? etc. I'm taking this opportunity to see how others purify small-moderate quantities

The other option is to use the anhydride, that is either methanesulfonic anhydride or trifluoromethanesulfonic anhdride. I actually prefer this and find that it is a much cleaner reaction. Both of these are commercially available, or can be simply prepared by distillation from P2O5. The reaction then just involves heating your alcohol in the presence of the anhydride, this can be done either neat or in an organic solvent such as MeCN. Check out this paper "The 1-Lactone Route to a Totally Stereoselective Synthesis of Carnitine Derivatives".Chem. Eur. J. 1996.2. No. 7 p826

TsIm, NaH

Go to mesylation

I have already use the formation of an hindered tosylate but without solvant according to F. Kazemi, A. Massah, M. Javaherian: Tetrahedron, 2007, 63, 5083.

If this method is not successful in your case, try to introduced a triflate.

Good luck

Go to mesylate instead off. Can you make the alkoxide ? If yes, then you can add the chloride!

Compared to the the Methyl group and macrocyclic ring the oAc will have less steric hindrance as it can rotate about O-C bond

If your idea of protecting the alcohol is to make it leaving group then you can go for MsCl rather than TsCl

If you want steric hindrance and leaving group than you can think of Nosyl chloride which is more reactive than tosyl due to the electron withdrawing NO2 group.

Be cautious that the nucleophilc displacement of the Ms or Ts or Ns may also result in elimination in the five member system such as lathyrane.

Also you can try the reaction at higher temp (RT-40) instead of the regular 0 oC

You can tosylate Sec-alcohol with P-Ts in an inert atmosphere of Nitrogen

You may try for the some other halogen tosylate moities .

Ex :p-tosyl bromide

p-tosylate bromide in inert gas like Nitrogen will give you better results

TsCl + NaI (cat.) + DMAP will do it

Alternative: Use MsCl + Et3N (gives the mesylate, via sulfene)

Tosyl chloride and organic base will work

Use NaH/DMF in Microwave for 5-10 mins, 60 deg C; then TsCl for another 5-10 mins in MW. You can do the same reaction under the hood also.

MsCl will be my choice as it is not as bulky..what is your ultimate aim in introducing a OTs, will you knock it off in the next step? e,g converting to halide?

What about Mitsunobu?

Good day, I have a question is possible to do mesylated secondary alcohol but this alcohol is very particular is benzyl vinyl alcohol, this product would be stable? thank yoy for the help

If You need to follow with a nucleophilic displacement, I suggest to try trifluoromethanesulfonate instead of tosylate. It is the best leaving group, more and more reactive than tosylate and mesylate.

Good luck

We have a good effective method for the protection of OH-groups of ecdysteroids and carbohydrates (including steric hindered). To a solution 1 mol of a substrate in THF sequentially was added 1.5 mol Me3SiCF3 (TMSCF3)and TBAF. The The mixture was stirred for a few minutes (TLC monitoring).Yield 80-90%.Good luck for you.

Use ultrasound at low temperature employing CH2Cl2 or CHCl3, this is useful for simple hindered OH or supramolecular hindered OH in polymers. The theoretical background behind is the enhancement of molecular collisions through ultrasound. Additionally employ almost stoichiometrical amounts of NEt3 (ca 1.03 mol per tosilated OH). Best regards and fruitful reactions.