Question
Asked 30th Apr, 2013

How can I tosylate an hindered secondary alcohol?

I'm trying to sterify with p-tosyl chloride (TsCl) a secondary alcohol. Although it is a simple reaction, it will not react, because the hydroxyl group is hindered. This group is located in a lathyrane scaffold, in the position C3 (ciclopentane ring), and seems that the macrocylic conformation and the acetyl group at C15 (2 bonds away) is preventing the reaction.
What can I do to increase tosylation?

Most recent answer

5th Oct, 2015
Hi Beltran
Metropolitan Autonomous University
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.

Popular answers (1)

9th Jul, 2013
Howard Black
Eastern Illinois University
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.
15 Recommendations

All Answers (65)

30th Apr, 2013
Laurent F Bornaghi
Mavlab Animal Health
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...
1 Recommendation
1st May, 2013
Ricardo J Ferreira
Red Glead Discovery
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
1st May, 2013
Laurent F Bornaghi
Mavlab Animal Health
You could try a different base, like DMAP or imidazole. I could change DCM for DCE so you can heat to a higher bp.
1 Recommendation
1st May, 2013
Musa Özil
Recep Tayyip Erdoğan Üniversitesi
You could try Amberlyst 15 for reaction hindered secondary alcohol
1 Recommendation
Deleted profile
Hi Ferreira. Maybe you can get your product using methanesulfonyl chloride plus DMAP and dry pyridine.
2 Recommendations
1st May, 2013
Chandra kanth p
Pandit Deen Dayal Petroleum University
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
1 Recommendation
1st May, 2013
Hi Beltran
Metropolitan Autonomous University
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.
1st May, 2013
Ricardo J Ferreira
Red Glead Discovery
@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
1st May, 2013
Alejandro Moll Urzúa
University of Santiago, Chile
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.
1 Recommendation
1st May, 2013
Mark Tallon
Technological University Dublin - City Campus
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.
1 Recommendation
1st May, 2013
Rimma G Savchenko
Institute petrochemistry and catalysis Russian Academy of sciences
you can to use another protective group.For example TMS-CF3/TBAF. we use trifluoromethyltrimethylsilylation for protective stericaly hindered hydroxy-groups of steroids
1 Recommendation
Deleted profile
You could try a method which utilizes TsCl/NEt3/cat. Me3N.HCl. See the attached paper.
1 Recommendation
1st May, 2013
Hi Beltran
Metropolitan Autonomous University
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
1 Recommendation
2nd May, 2013
Matej Babjak
Slovak University of Technology in Bratislava
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.
2 Recommendations
2nd May, 2013
Gabriele Marcolongo
Epitech Group
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.
2 Recommendations
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.
1 Recommendation
2nd May, 2013
Artur R. Abreu
C. M. laboratories
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.
1 Recommendation
3rd May, 2013
Adilson David Da Silva
Federal University of Juiz de Fora
I agree with Matej Babjak, DMAP in DMF is good as catalyst.
1 Recommendation
3rd May, 2013
Ameen Abuhashem
National Research Center, Egypt
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,,,,,,,,,,,,,,,,,,,,
2 Recommendations
Deleted profile
You can try diethyl
azodicarboxylate-triphenylphosphine-formic acid inversion
1 Recommendation
Deleted profile
You also will produce a mixture of isomers if you warm the solution of your secondary alcohol with DMF, p.e., 80oC for a couple hours
1 Recommendation
Deleted profile
Diethyl
azodicarboxylate-triphenylphosphine-formic acid inversion can be useful if your target compound will be the inverted alcohol...
1 Recommendation
5th May, 2013
Rupesh Betkar
University of Mumbai
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
1 Recommendation
7th May, 2013
Ghrab Saad
University of Tunis
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
6 Recommendations
7th May, 2013
Deepak Kumar Aneja
Chaudhary Bansi Lal University, Bhiwani
You can use HTIB (Koser's reagent) for for tosyloxylation by ligand exchange reaction.
1 Recommendation
22nd May, 2013
Oliver Schwarz
AnalytiCon Discovery GmbH
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
1 Recommendation
8th Jun, 2013
Dr Mohammad Mahboob Alam
Albaha University
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.
1 Recommendation
8th Jun, 2013
Haruhiko Fuwa
Chuo University
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.
1 Recommendation
10th Jun, 2013
John W. Harder
Kodak
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.
14 Recommendations
12th Jun, 2013
Sankara rao Kola
Micro Labs
Better reagent for peptide formation DCC,HOBT , Organic Base (Et3N) and Media MDC .
2 Recommendations
12th Jun, 2013
Qi Wang
University of Turku
I suggest to use Ghrab Saad's method. It is simple and high yield. The purification is easier. Good luck!
2 Recommendations
22nd Jun, 2013
Teodoro S Kaufman
National Scientific and Technical Research Council
Add iodide (KI. NaI), and perhaps 16-C-6; use HMPA as solvent, DMAP as promoter and DIPEA as base. Good luck!
2 Recommendations
25th Jun, 2013
Amjid Iqbal
Qassim University
I would recommend mesylation instead of tosylation
4 Recommendations
28th Jun, 2013
James Demers
Cittone, Demers & Arneri LLP
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.
4 Recommendations
2nd Jul, 2013
Po-wai Yuen
Pharmaron
Try dissolving your alcohol in anhydrous DMF, add Ts2O, cool the reaction mixture to 0 degree C then slowly add NaH.
2 Recommendations
7th Jul, 2013
Jason Mann
Rice University
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.
2 Recommendations
9th Jul, 2013
Howard Black
Eastern Illinois University
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.
15 Recommendations
9th Jul, 2013
Arnaud Gautier
Université Clermont Auvergne
Use the Hanessian's trick: imidazoles sulfonate in place of Tos. Tetrahedron 1996, 10557. Usually that works better.
6 Recommendations
7th Sep, 2013
Umangkumar Harishchandra Shah
Charotar University of Science and Technology
The attached publication may help you
1 Recommendation
7th Sep, 2013
Umangkumar Harishchandra Shah
Charotar University of Science and Technology
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
11th Sep, 2013
Jur Wildeman
University of Groningen
try DMF/THF 4/1, with 5 fold excess of K2CO3, at 50-60 degrees, for 2 days
11th Sep, 2013
Lebusetsa Taleli
University of Cape Town
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!
11th Sep, 2013
Florenci González
Universitat Jaume I
HIndered secondary alcohols can be very difficult to tosylate. I would advice mesylation or halogenation instead.
1 Recommendation
25th Jan, 2014
Derisvaldo R. Paiva
cefet -rj
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!
28th Jan, 2014
Nicholas Coffey
The Harvard Drug Group
@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
29th Jan, 2014
James Robert Cochrane
Ecole normale supérieure de Lyon
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
7th Feb, 2014
Gordon J Florence
University of St Andrews
TsIm, NaH
10th Feb, 2014
Antonio Mouriño
University of Santiago de Compostela
Go to mesylation
12th Feb, 2014
Christine Saluzzo
Université du Maine
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
12th Feb, 2014
Antonio Mouriño
University of Santiago de Compostela
Go to mesylate instead off. Can you make the alkoxide ? If yes, then you can add the chloride!
7th Mar, 2014
Lourdusamy Emmanuvel
Karunya University
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
8th Mar, 2014
Madhukar Baburao Deshmukh
Shivaji University, Kolhapur
You can tosylate Sec-alcohol with P-Ts in an inert atmosphere of Nitrogen
27th Mar, 2014
Manuri Brahmayya
Academia Sinica
You may try for the some other halogen tosylate moities .
27th Mar, 2014
Manuri Brahmayya
Academia Sinica
Ex :p-tosyl bromide
27th Mar, 2014
Manuri Brahmayya
Academia Sinica
p-tosylate bromide in inert gas like Nitrogen will give you better results
1 Recommendation
27th Mar, 2014
Teodoro S Kaufman
National Scientific and Technical Research Council
TsCl + NaI (cat.) + DMAP will do it
Alternative: Use MsCl + Et3N (gives the mesylate, via sulfene)
2 Recommendations
28th Mar, 2014
Shiv Kumar Yadav
Surya World
Tosyl chloride and organic base will work
1 Recommendation
9th Apr, 2014
Boobalan Pachaiyappan
Northwestern University
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.
5th Jun, 2014
Anuradha Gupta
Syngene International Ltd.
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?
1 Recommendation
2nd Oct, 2015
Diana Soto
University of Alabama
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
2nd Oct, 2015
Gabriele Marcolongo
Epitech Group
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
1 Recommendation
4th Oct, 2015
Rimma G Savchenko
Institute petrochemistry and catalysis Russian Academy of sciences
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.
5th Oct, 2015
Hi Beltran
Metropolitan Autonomous University
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.

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