Org Prep Daily

July 24, 2008

Lime (and Pt-C)

Filed under: procedures — milkshake @ 9:34 pm

A slurry of calcium hydroxide 5.18g (70mmol) in a neat mixture of 2-chloro-3-nitrotoluene 6.580g (38.34mmol) and 4,4-(ethylenedioxo)-piperidine 13mL (100mmol) was stirred without solvent in a closed pressure glass flask at 180C for 10 hours (overnight).  The flask was cooled to ambient temperature, the sludge was diluted with ether 100mL and briefly sonicated to break the lumpy solids. The inorganics were removed by filtration, washed with additional ether (150mL) and discarded. The combined filtrates were washed with 1M aqueous citric acid (2x200mL), then with water (200mL) and saturated NaHCO3 (200mL). The aqueous phases were re-extracted with ether (200mL). The combined extracts were dried (MgSO4) and evaporated. The obtained oil was dissolved in cyclohexane 50mL and the solution was left to RIP at RT for 1 day. Decanting the supernatants and washing the deposited chunky orange crystals with pentane and in vacuo drying provided 7.762g of a pure product. The combined supernatants and pentane washings were passed through a 2x2inch pad of silica, the silica was then washed with dichloromethane 150mL and the combined filtrates were evaporated. The evaporation residue was re-crystallised from cyclohexane 10mL to provide the second crop, 1.312g of pure product as a bright-yellow gem quality rhombs.
The combined yield was 9.074g (85%Y).

This nitro-compound, 7.760g (27.88mmol) was then hydrogenated in the presence of 5% platinum on carbon, 0.51g [Aldrich 205931] in ethyl acetate (150mL) at RT under hydrogen balloon for 3h 30min. The mixture was filtered through a pad of Celite to remove the catalyst (the pad was washed with additional EtOAc) and the filtrates were evaporated. The crystalline residue was dried on highvac. Y=6.860g (99%) of a white crystalline solid.

1H(d6-DMSO, 400MHz): 6.704(t, 7.6Hz, 1H), 6.496(dd, 7.8Hz, 1.2Hz, 1H), 6.253(d, 7.2Hz, 1H), 4.857(br s, 2H), 3.905(m, 4H), 3.204(td, t:11.5Hz, d:2.3Hz, 2H), 2.786(br m, 2H), 2.195(s, 3H), 1.812(td, t:11.7Hz, d:4.6Hz, 2H), 1.655(br d, 11.1Hz, 2H); 13C(d-6DMSO, 100MHz): 145.63, 135.66, 134.76, 125.45, 118.91, 112.15, 106.61, 63.64, 63.52, 47.24(2C), 35.97(2C), 19.41


  1. 5% Pt-C: is it a better catalyst than 10% Pd-C?

    Comment by pmgb — July 24, 2008 @ 10:58 pm

  2. 5% Pt-C is a lot faster and cleaner than 10% Pd-C for nitro reduction and for non-conjugated alkene C=C saturation. Also platinum does not cleave benzyllic ethers/esters or benzylamines.
    Platinum is gentle to halogens on benzene ring: one can hydrogenate polychloro/fluoro-nitro benzenes or even bromo-nitrobenzenes to anilines in EtOAc under a baloon without the halogen loss (the reaction has to be monitored and stoped in the right moment though).

    The platinum-catalyzed ring saturation does not seem to be a problem with the benzene ring at atmospheric pressure of H2 and neutral conditions, many heterocycles are more sensitive to Pt than Pd but we have been hydrogenating nitropyrazoles on Pt-C without problem. Pt-C catalysts perform well at considerably lower metal loadings than Pd-C.

    Pd-C became the most popular hydrogenation catalyst because of its low cost – but lately Pd has been very dear also. One can actualy save money nowadays by switching to Pt-C because of its much higher activity with some substrates.

    Comment by milkshake — July 24, 2008 @ 11:25 pm

  3. Hey Milkshake,

    In the first step, you washed with citric acid. Do you perform the citric acid wash to ensure that any hydroxides are removed, or does it serve another purpose?

    Comment by Steve — July 25, 2008 @ 1:21 pm

  4. Hi MS,

    Seems very good reaction (Reaction involving Calcium hydroxide)and easily Scalable for Process chemist!!! Could you please let me know any lead referance for this type of reaction ?



    Comment by Marto — July 25, 2008 @ 2:20 pm

  5. The citric acid wash was there to get rid of leftover salts (most were removed by filtration before) and especially to extract the excess of the piperidone spiroketal. The nitroaryl piperidine product is pretty non-basic and the ketal is rather stable so citric acid does it no harm. Also citric acid is much les ether soluble than in EtOAc.

    I don’t have any limey reference. The reason why I had to add a base was that amine hydrochloride is unfortunately acidic enough at these drastic reaction conditions (180C, overnight) to ruin the spiroketal protecting group – and a hindered amine like iPr2NEt was not good enough to prevent this spoilage at higher conversion, due to the accumulated amine HCl salts. Nitrotoluenes are unfortunately also base-sensitive at these high temperatures, they gladly make crap from DBU etc, so I needed some base that was not nucleophilic. Alkali carbonates worked but the outcome wes very dirty so I tried calcium hydroxide (because I had a big jar of it from the previous project) and it went much better. Maybe calcium carbonate would also do the trick, I have not tried it.

    Ca(OH)2 comes also useful when you need to liberate a water-soluble amine from diluted sulfuric acid and you are looking for an alternative to ion excanger resins… It is also strong enough base to deprotonate phenols and amides.

    I have to quell your entusiasm though – with big reactors, little problems like a formation of a sticky precipitate can make all the difference- for worse. You have to test scalability before you decide to load up with lime.

    Comment by milkshake — July 25, 2008 @ 6:42 pm

  6. milkshake this is interesting twist on the often difficult nucleophilic displacement of an ArCl. Have you done variation in the amine? Sterically and otherwise I seem to recall piperdine typically makes a better nucleophile that most amines and in your case acceptor is crowded by the 3-Me.

    Per Marto seeming promise for plant ops, my concern on scale-up is the pressure requirements. 180C accessable but special reactors needed to run pressures. Presumably could work out a solvent system to handle sticky pcpt.

    Though not needed here I learned a trick to clean/activate “old” Pd-C was either simple wash with hexane or heptane (swirl/decant 1-2x) or better yet suspend then heat briefly in one of those solvents(up to reflux). Appeared to require less cat. load, faster and cleaner in comparison case tried (then always performed routinely thereafter).

    Comment by CMC guy — July 25, 2008 @ 10:57 pm

  7. milkshake: how does Ca(OH)2 help liberate an amine from dilute aqueous acid (for example over any other hydroxide like sodium)? Doesn’t calcium sulfate just precipitate out and make a mess?

    Comment by Jason — July 26, 2008 @ 9:50 am

  8. when your amine is very soluble even as a free base (so you cannot extract it) you can use the Ca(OH)2 trick – you filter out the mess of CaSO4.2H2O together with the excess of Ca(OH)2 and you are left with little inorganics in the supernatants – you filter, evaporate, column or Kugelrohr it, etc. No salts.

    Halogen -o,p-substituted pyryidines, pyrimidines and nitrobenzenes (and fluoro-sunstituted benzonitriles and benzoic acids) displace directly halogen with amines, and F is much better leaving group than Cl (which is much better than I, Br) in these non-catalyzed SN-Ar reactions. This is not new.

    In this particular case the halide was not as reactive (2,3-dichloronitrobenzene and especially 2,3-difluoronitrobenzene works much better, in this case the corresponding fluoro compound with methyl was not commercial.) so the non-catalysed reaction had to use quite severe conditions. The crap up was not as bad with Ca(OH)2 and the product crystallised very nicely.

    Piperidine vs other amines: I think the most reactive amine is MeNH2, followed by pyrrolidine and then by morpholine, but piperidine and dimethyl amine are of course very good also.

    Comment by milkshake — July 27, 2008 @ 12:36 pm

  9. Speaking of reductive Pd and Pt, I’ve been trying to selectively remove a N-benzyl group in the presence of a benzonitrile. Unfortunately, all the conditions tried so far (Pd and 1 atm H2) have removed the protecting group AND reduced the nitrile all the way down to a CH3 group. Does anyone know a catalyst system that avoids reducing nitriles?

    Comment by Jason — July 29, 2008 @ 1:45 pm

  10. I am sorry but you cannot have a nitrile there for reductive debenzylation, as you now know. The only good options for reductive debenzylation are Pd and Na/NH3(liq) (or Li/NH3(liq), for reductive debenzylation, and they will both eat the nitrile first.

    You may try oxidative de-benzylation with 4 equivs of cerium ammonium nitrate (in aqueous acetonitrile 0C to RT) or DDQ, to cleave off your benzyl as benzaldehyde. This is not a very fast (or clean) debenzylation though – it would go much better if you had p-methoxybenzyl there instead. And the MW of CAN is huge.

    There is also acid-promoted debenzylation, but you will probably need extremely strong acid like TfOH or HF and a scavanger, and this is going to hydrate your nitrile to amide (maybe you can add trifluoroacetic anhydride to keep it from hydrating). Another good anhydrous alternative to triflic acid is TFA+BF3.Et2O mix – and it is easier to evaporate.
    Benzyl ethers can be sometimes cleaved with TFA+thioanisole (1% by volume) which would be compatible, but you may need like 60C overnight and PhSMe reeks.

    Comment by milkshake — July 29, 2008 @ 2:46 pm

  11. N-benzyl or N-methyl amines can be cleaved using ACE-Cl (chloromethylchloroformate), see for example Tetrahedron, Volume 62, Issue 50, 11 December 2006, Pages 11679-11686. It is fairly general.

    Regarding the hydrogenation, Johnson Matthey folks can help you with a suitable catalyst or Pd form to avoid CN reduction. You can ask them if this is important for you. They can even send you a free catalyst sample to test the reaction.

    Comment by vasili — July 29, 2008 @ 4:37 pm

  12. The Johnson Matthey folks rock. They really have their act together; if you are in industry and flush with cash, look into their “spice rack” with 20 or 30 different hydrogenation catalysts, with all kinds of unexpected selectivities so you can optimize like a fiend.

    Comment by Jose — July 30, 2008 @ 5:09 pm

  13. This one published here:

    Comment by ChemSpiderMan — March 25, 2009 @ 10:10 pm

  14. I am trying to reduce 8-nitro-4-oxo-1,4-dihydroquinoline into the corresponding amino compound. Tried few conditions ((i) Pd/C, H2, MeOH (or) EtOAc (ii) Amm formate/Zn and also Amm formate/Pd but obtained the reduced product with 30-35% yield along with inconclusive product. The reaction is OK on small scale but work up problems on higher scale.

    Planning to try sodium dithionite reduction and Pt/H2 reduction. I need to prepare 50.0 g of reduced product. It could be expensive to use Pt catalyst.
    please suggest me any other conditions if you have some experience.



    Comment by marto — April 13, 2011 @ 1:02 am

    • I would definitely go with Pt-C, in EtOAc as a solvent, at atmospheric pressure. Pt catalyst is much more faster and usually cleaner than Pd-C for nitro reductions and often you could use only very little of it.

      Also Raney nickel is very good option for reducing nitros, it works well with hydrogenation on Parr shaker. You can also do atmospheric-pressure Raney nickel transfer hydrogenation in reluxing ethanol, by adding hydrazine hydrate (dropwise- be carful!) as a hydrogen source. Raney Nickel catalyst catches on fire easily when it dries so please be careful with handling the catalyst

      Comment by milkshake — April 13, 2011 @ 8:58 am

  15. Thanks very much for the suggestions.



    Comment by marto — April 14, 2011 @ 6:01 am

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