Org Prep Daily

June 22, 2010

(S)-6-methoxychromane-3-carboxylic acid by asymmetric hydrogenation

Filed under: procedures — milkshake @ 1:13 pm

6-methoxychromene-3-carboxylic acid 6.186g (30 mmol) and (R)-octahydro-BINAP.RuCl2.1/2Me2NH2+Cl- complex 26mg [from Strem, Takasago-made] (0.030 mmol Ru) was loaded into a 300mL-sized Ace glass pressure hydrogenation flask with teflon screw-cap and a rod stirbar. The gas inlet was equipped with a rubber septa and the solid mix was flushed with a gentle stream of argon (15 min). A solution of cesium formate 21.35g (120 mmol) in methanol 120mL in a septum-fitted round flask was deoxygenated by argon sparge on ultrasonic bath (15 min bubbling) and the solution was transferred into the hydrogenation flask via thick canula under Ar.  The Parr hydrogenator gas inlet was connected to the flask, the flask was placed on ambient bath on a stirplate behind a blast shield and the argon was replaced with hydrogen (5-times vacuum/hydrogen purge). The heating was turned on and the mixture was stirred at 40C under 100 psi (=7 atm) of hydrogen for 20 hours.  The resulting colorless homogeneous mixture was cooled to ambient temperature, carefully vented, transferred into a 1L round flask and evaporated to dryness. The residue was diluted with water 200mL and dichloromethane 200mL, acidified with 6M HCl (30mL) , shaken and separated. The aqueous phases were re-extracted with additional dichloromethane 200mL. The organic extracts were washed with water 200mL, combined, dried (MgSO4) and evaporated to provide 6.30 g of white solid, 89% ee (by chiral HPLC, Note 1).

This not-quite pure (S) acid was dissolved in acetonitrile 1.75L. The solution was brought close to reflux and (S,S)-chloramphenicol base 6.360g (30 mmol) was added in one portion (the funnel was washed with additional MeCN 30mL) and the mix was stirred at gentle reflux until complete dissolution (15 min). The mix was then allowed to crystallize at ambient temperature overnight (16 hours) . The precipitated salt was collected by filtration, washed with MeCN and dried by suction to provide 11.008g of a pale yellow solid (87.5% th, 99% ee, Note 2). This chloramphenicol base salt was combined with ether 250mL and water 200mL, acidified with 6M HCl 10mL and stirred for 10 min, then separated. The aqueous phase was re-extracted with ether 250mL. The organic extracts were washed with water 250mL, combined, dried (MgSO4) and evaporated. The residue was dried on highvac. Y=5.455g (87%) of a white crystalline solid, 99% ee

Note 1: Chiral reverse phase column CHIRALPAK AD-RH was used at 0.85mL/min flow, column thermostat temperature 70C, in water-acetonitrile shallow gradient about 15-20% MeCN, with 0.1% TFA present in the buffer. The S enantiomer elutes first followed by R .

Note 2: If the chloramphenicol base salt is re-crystallized from acetonitrile for the second time, a product with no detectable minor enantiomer (>99% ee) is obtained. But the recrystallization takes quite a lot of acetonitrile, and 99% ee was good enough

Note 3: 100 psi is more than what is recommended for the Parr shaker equipment – it is certified only up to 50 psi… I managed behind a protective shield without a mishap but using a steel autoclave would be probably a safer alternative. There is almost no conversion if the hydrogenation is attempted under H2 baloon.

Note 4: (S,S)-Mandyphos-SL-M004-1 in combination with [Rh(NBD)2]BF4 at subst/catalyst 100:1 ratio gave with this substrate 84-85% ee of (R) enantiomer in MeOH at room temp and 100psi H2 within 2 h 15 min and complete conversion, and no formate additive was necessary. The Rh+ source salt is however fairly air-sensitive as a solid and the active pre-catalyst solution of the phosphine-Rh complex in MeOH is tricky to handle without a glovebox: I had reproducibility problems with hydrogenations run at low catalyst loadings – the hydrogenations often stalled. On the other hand, the octahydroBINAP-RuCl2 complex comes ready-made, it is stable enough to  be weighted out in air – and it can be loaded as a solid. (Unlike Ru-acetate-phosphine complexes, Ru-halide-phosphine complexes are robust but lazy. The exchange of halide with formate activates them in situ). Other formate salts such as HCO2Na can be also used, and less than 0.5  equiv of formate is needed but adding more formate salt seems to improve the ee  by few %. Cs-formate is readily soluble in methanol and it also appears to provide a marginally better ee.

The starting chromene acid preparation is described here


  1. Hi MS, 70C seems quite high, I think the recommended range is 5-40C.

    Comment by Chiral 1 — June 22, 2010 @ 2:28 pm

    • I totally agree – it will ruin the column over time but this was the only column that we had and in order to get a baseline separation between the two enantiomers I had to heat up. Sometimes compounds that are too greasy do not separate well on CHIRALPAK AD-RH (because they need too high acetonitrile % to elute) and this is the way around it.

      I was running 20 min runs including the re-equilibration and would heat up the column for the minimum needed time, less than 1 hour total. By the way there is always some crap coming off this column at the end of the acetonitrile wash ramp, regardless of the temperature

      Comment by milkshake — June 22, 2010 @ 3:21 pm

      • Hey, that’s part of the business model — if you sell columns that last forever, you gonna be out of business pretty soon ;-)

        For a greasy compound I’d like to start with normal phase (Hept/EtOH) and for an acid like in your case, add 0.1-0.2% formic acid. Then screen Chiralpak-s IA, IB and IC (in that order).

        Anyway, glad it worked. Just wanted to warn you: 12 years ago, as a rookie I killed two $1200 (each) OF columns in one day, good thing I had a good boss, so I didn’t get fired. (Back in ex-Eastern EU they’d have probably taken the money from my paycheck, for the next 5 years :-)

        Comment by Chiral 1 — June 22, 2010 @ 7:35 pm

      • I think the straight phase chiral columns are much easier to mess up, by putting a wrong solvent mix on them: you do it just once and they are gone. Reverse-phase chiral column can survive an absentminded operator – it only degrades faster. (I am still rather unhappy about my former colleague who left our chiral column parked at 60C overnight, with exchanged mobile phases – despite me asking him repeatedly to bring the column back to low temp at the end of his work and re-equilibrate it – and he was then acting surprised when I complained about it)

        Comment by milkshake — June 23, 2010 @ 8:08 am

  2. on the subject of chiral resolution: i need to separate two alcohols (diastereomers) after an asymmetric ketone reduction. chromatography is tricky so far, any ideas on resolving agents for alcohols? cheers!

    Comment by medchem — June 22, 2010 @ 7:39 pm

    • Does your compound have any amines to make a salt with? I’m assuming not. How functionally complex is your molecule?

      A chiral (phenylethyl) isocyanate could do the trick.

      Comment by T — June 22, 2010 @ 10:33 pm

    • mosher’s acid worked very well for me

      Comment by james — June 24, 2010 @ 11:40 pm

  3. No amines, no acids. So far only 2 stereocenters and no functional groups (a side from the -OH)

    Comment by medchem — June 23, 2010 @ 3:28 am

    • since the alcohols are diastereomeric, your derivatization reagent does not need to be chiral. I would try any number of protecting groups that are easy to introduce and remove under mild conditions. For example acetate or benzoate ester or TBS silyl ether. If your desired isomer is the main one, you can try to get a crystalline derivative and re-crystallize it, I have always had a good luck with removing minor diastereomers by recrystallizations but of course the more of the undesired diastereomer you got there the bigger is the penalty on the yield – the stuff that you are crystallizing away will take with it some of the main product into the supernatants and at some point you get to the isomeric ratios that they wont separate by recrystallization any longer. Para-substituted benzoates (p-toluoyl, p-nitrobenzoyl, etc) are particularly good for getting crystalline derivatives.

      Comment by milkshake — June 23, 2010 @ 7:58 am

  4. Greetings MS,

    I am trying to Decarboxylate few heteroaromatic (pyridine core with alkyl substitutions – COOH at 3-position) carboxylic acids. Tried few conditions (Heating at 250 °C in diphenylether – no conversion, decarboxylation using silver carbonate gave inconclusive mixture). Please suggest me any conditions if you have any experience.

    I am trying the reductive cyano removal of heteroaryl cyano compound (Pyridyl core with EDGs – CN group at 3-position) also but unsuccessful so far. Please suggest me any conditions if you have any experience.



    Comment by marto — June 24, 2010 @ 3:49 am

    • I don’t think you can burn off cyano group from pyridine reductively. You will reduce pyridine ring easily though/
      Decarboxylation: It wold have been easier if the carboxy was in the 2-position on your pyridine ring, when you heat pyridine-2,3-dicarboxylic acid the carboxyl in the 2-position falls of selectively, the carboxy in the 3-position stays. This is how nicotinic acid is made from quinoline.
      I do not have any experience with decarboxylating pyridinecarboxylic acids. I remember that these reactions are catalyzed by Cu(I) salts but even then one still needs to heat very high. You need to find a close literature precedent…and if you cannot find any it is a sign that you are either doing something very esoteric (that no-one ever tried before) or that you are attempting something that could not be done before.

      Comment by milkshake — June 24, 2010 @ 9:20 am

  5. Hi Guys,
    which is the best way to achieve metal-halogen exchange with 5-Bromoindole/3-Bromocarbazole?I tried (t-BuLi, THF, -80 c then DMF), only poor conversion.
    Thank you so much.

    Comment by madforit — June 24, 2010 @ 9:44 am

    • I have not done this myself but I would protect the acidic NH, by silylation with iPr3SiCl + NaH (or DBU with DMAP) and then do the lithiation with some base that is less likely to bring about CH direct lithiation – apparently indoles like to get lithiated on the pyrrole ring with stuff like tBuLi. Maybe nBuLi would be a better choice and if the Br to Li exchange is still messy with BuLi alone I would try Knochel conditions with BuMgCl + LiCl or BuMgCl + BuLi at -40C to -20C.

      Comment by milkshake — June 24, 2010 @ 11:56 am

    • With the NH protected as suggested above, you could use lithium metal plus naphthalene to pre form the Li napthalenide (or one of the other alternatives such as 4,4′ di-t-butyl biphenyl – J. Org. Chem. 55, 1528, (1990). then you can do the metal-halogen exchange without the strong base being present.

      However even if you make the 5-lithio derivative of the indole in this way, it could then exchange/deprotonate at the 2 position if this CH is more acidic (I don’t have the pKas in my head, abut will clearly depend on what you protect the N with).

      Comment by Fleatamer — June 25, 2010 @ 5:00 am

    • I would use 1.1 equivalent of MeLi then 1.1 equivalent of BuLi (n- or t-)to first deprotonate then do the exchange at low temperature (-78 C). This has worked quite well for me in the past.

      Comment by JML — June 30, 2010 @ 4:02 pm

  6. Thanks very much for the help.

    Comment by marto — June 25, 2010 @ 12:42 am

  7. Sorry for the previous post,
    i will try the N-TIPS protection on 3-Bromocarbazole,
    then with t-BuLi at – 80 to -40 C.
    Thank you so much.

    Comment by madforit — June 25, 2010 @ 3:45 am

  8. Funny, I’m prepping my poster for the Gordon Organometallics Conference, and geez, my schemes are full of lithiated aryls and heteroaryls. :D iPrMgCl DOT LiCl might also do the trick. (Angew Chem Int Ed, 2004, 43, 3333-3336).

    Anyone from the faithful readership plans to be there, BTW?

    Comment by HPCC — June 25, 2010 @ 3:37 pm

    • I would attend it but my management did not approve to cross the puddle for that so we have to stick to the old continent’s.

      Comment by Vasili — June 26, 2010 @ 9:21 am

  9. Thanks a lot!!

    Comment by madForIt — June 26, 2010 @ 11:55 am

  10. The above poster mentioned methyl vinyl ketone I think, what would the risks be if I spilled a drop of that on my skin?

    Comment by LabRat — June 27, 2010 @ 1:25 pm

    • 1) methyl vinyl ketone is unhealthy (an electrophile). A drop of MVK it will not kill you, it is not a warfare agent but working with boatloads of MVK on a daily basis carelessly and ingesting the stuff over the long term can eventually give you children born with two heads or leukemia 2) what you drew above is not MVK – you drew the structure wrong
      I noticed that all these rather naive-sounding questions are coming from the same IP address so I presume you are also the person who has asked here about the silyl enol ethers – if this is so you should use only one nickname and stick with it. I appreciate that you are reading this web page but since you are posting off-topic comment-questions all the time please try to not to be too demanding – especially since the chemistry problems that you keep asking about are at the entry level; I am sure any colleague in your lab can answer them for you.

      By the way, if you are nervous about nasty chemicals maybe you should not do synthetic organic chemistry. You can specialize in another subfield, something like spectroscopy – its clean, high-tech equipment, and it is very intellectual and esoteric. NMR specialists and X-ray crystallographers are highly respected and they have much better job prospects these days than synthetic chemists.

      Added note: I just removed your three latest comments, and most of your previous comments too, and I added you on a comment spam list. Please take it easy.

      Comment by milkshake — June 27, 2010 @ 2:22 pm

  11. Dear MS,

    I am trying to do asymmetric hydrogenation of similar system instaed of COOH group contains an aryl group. I am wondering whether such a catalyst can work for my system. Please let me know if you have any suggestions. I have reports for Iridium catalyst but no reports of other metals.



    Comment by marto — November 24, 2013 @ 1:19 pm

    • I don’t think you can use this system. For successful Ru-catalyzed asymmetric hydrogenation you need to have at least one metal-coordinating group (carboxy, in this case). Two coordinating groups work even better – the first classes of substrates for wich these Ru systems were successfully used were beta ketoesters (reduction of the keto group to alcohol) and alpha-acetamido cinnamic acids (C=C reduction). Since I am not quite up-to-date with latest developments in asymmetric hydrogenations, and since the literature is so large, and since asymmetric reaction development is pretty non-trivial problem (even with a good precedent and good analytic methodology available – chiral GC or chiral HPLC – the asymmetric procedure can take 6 months of one-man work, to develop into scalable process stage) I recommend that you start with a thorough literature search, going back about 25 years, get the closest precedents, then look for alternatives that use low pressure (if you can find any). Seriously, this is a rather difficult problem and you may want to hire someone who has done something similar in the past.

      Comment by milkshake — November 24, 2013 @ 4:33 pm

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