Org Prep Daily

August 18, 2008

Chromenes: Baylis-Hillman-derived cyclization

Filed under: procedures — milkshake @ 11:01 pm

 

DABCO, 1,4-diazabicyclo[2.2.2]octane 4.5g was added to a mixture of 2-hydroxy-5-methoxybenzaldehyde 26.60g (174.8 mmol) and neat acrylonitrile 20mL. The mixture was diluted with additional acrylonitrile 40mL (5.2 eq. total) and refluxed on a 110C oil bath for 5 hours. (Note 1,2). The reaction mix was cooled to RT, diluted with ether 0.5L, shaken with 10% NaOH aq solution 250mL for 5 min then separated. The org phase was washed sequentially with water (250mL), 0.5M sulfuric acid (250mL) and then more water (2x250mL). The aqueous phases were re-extracted with ether (250mL). The combined org. extracts were dried (MgSO4) and evaporated. The solidified residue was dried on highvac. The crude product (a yellow solid, 30.2g) was re-crystallized from methanol (140mL, at 0C overnight, rinse with chilled MeOH) to provide 19.223g of a pure material (98%+) as light-yellow crystals. Evaporating the supernatants and re-crystallising the residue from methanol (50mL, -20C overnight) provided a second crop, 2.827g (96% pure by HPLC). A third crop 1.998g (97% pure) was obtained from the second supernatants (evaporation residue recryst from MeOH 20mL, -20C). The combined yield was 24.048g (73.5% th)

1H(d6-DMSO, 400MHz): 7.537(br s, 1H), 6.896(m, 3H), 4.803(d, 1.3Hz, 2H), 3.714(s, 3H)

24.00g of the nitrile from previous step (128.2 mmol) was combined with aq. solution of NaOH 40g in water 400mL(total volume).  The slurry was stirred vigorously under reflux on a 120C bath for 5 hours. Charcoal 1g was added, the mix was re-heated to reflux briefly, then cooled to ambient temperature and filtered (the charcoal was washed with additional water until the filtrates were no longer yellow). The combined filtrates were made strongly acidic with  conc. HCl (150mL, exothermic), the resulting slurry was cooled on ice bath, the precipitate was collected by filtration, washed thoroughly with water, dried by suction and then on highvac. The crude acid was dissolved in refluxing acetonitrile (0.6L), allowed to sit for 5 min, then rapidly filtered through a large Buchner funnel while hot and the Buchner funnel was rinsed with additional hot MeCN  (approx 10mL), the combined filtrates were re-heated to full dissolution and the mix was allowed to crystallize overnight. Filtration and a rinse with cold MeCN provided the first crop 18.546g as golden-yellow needles. The second crop 4.392g was obtained by evaporating the supernatants and re-crystallising the residue from MeCN 120mL. The third crop 0.888g was obtained analogously (from second supernatants, re-cryst from MeCN 20mL, yellow plates). The combined yield was 23.826g (90%Y) of a pure acid.

1H(d6-DMSO, 400MHz): 12.821(br s, 1H), 7.422(s, 1H), 6.957(d, 2.9Hz, 1H), 6.849(ddABX, 8.7Hz, 2.9Hz, 1H), 6.785(dAB, 8.8Hz, 1H), 4.827(d, 1.4Hz, 2H), 3.704(s, 3H)

Note 1: Acrylonitrile is a potent irritant – and a good carcinogen too. Use gloves, avoid the vapors. Asthmatics keep their inhaler at hand.

Note 2: The original procedure calls for 20 h reflux. In my hands there was no further change after 3 hours reflux on a 110C bath – so I eventually stopped it at 5 hours because DABCO also catalyzes acrylonitrile dimer formation. Fluka acrylonitrile (BHT stabilised material) was used straight from the bottle.

7 Comments »

  1. I love bottles of acrylonitrile that say “WARNING: CONTAINS ACRYLONITRILE”

    That’s not a warning. That’s a blessing. It should say “HOORAY! CONTAINS ACRYLONITRILE”… until it polymerizes, then it should way “WARNING: CONTAINS SHIT”

    Comment by excimer — August 19, 2008 @ 2:25 am

  2. Also: how easy would it be to oxidize that carbon alpha to the chromene oxygen? It’d be a lovely way of making some interesting coumarins if it were an easy task…

    Comment by excimer — August 19, 2008 @ 10:30 am

  3. Long before Enviro-whiner oxygenates destroyed all engine elastomers folks were hard put to create a rubber hose that resisted hydrocarbon fuels. Synthetic rubber copolymerized with vinyl cyanide (polar!) did the trick. Even WWII could not justify railroad tank cars shipping vinyl cyanide.

    The chemist was told to get his butt back in the lab and find something else that worked. A week later acrylonitrile was found to equal vinyl cyanide in every way, hence nitrile rubber.

    Comment by Uncle Al — August 19, 2008 @ 11:21 am

  4. I think for making coumarins, using the same aldehyde with malondiester or cyanoacetate ester in Knoevagel-like cyclization would be a more direct way. (This one goes back all the way to Perkin. If I remeber correctly acetic anhydride with NaOAc works fine for the purpose.)

    Comment by milkshake — August 19, 2008 @ 3:49 pm

  5. Hi MS,

    I am sturggling to hydrolyse hindered aryl nitrile in presence of sulfonamide group. Could you please suggest me any suitable conditions for this conversion? and also would like to convert this acid into the corresponding acid chloride? do you reckon sulfonamide wont be reactive this reaction?

    Thanks

    Marto

    Comment by Marto — September 21, 2008 @ 2:49 pm

  6. Is your sulfonamide tertiary or secondary? RNH-SO2R is resistant to harsh alkaline conditions but R2NSO2R is not (the sulfonamide NH deprotonates and that keeps it from hydrolysis).

    I would try stepwise hydrolysis: first to get a primary amide from the nitrile. Then I would hydrolyse the amide to acid under carefully monitored conditions.

    To make the primary amide I would use sulfuric acid (90% H2SO4, dissolve on ice bath, then stirr at RT and monitor on HPLC, you can gradually heat up to 60C if it does not work at RT) or LiOH+H2O2 (dissolve the nitrile in a mix of THF + 10-20 equivs of H2O2 as 15% soln and add 1M solution of LiOH.H2O in water, few equivs, dilute down with some water if lithium peroxide hydrate precipitates, stirr at 0C or allow to warm up to RT; the final concentration of H2O2 about 5-10% and about 50% THF by volume).

    Then I would take this primary amide and try to hydrolyse it in 6M HCl , by raising the temperature gradually (while watching the progress on HPLC to supress the over-hydrolysis of the sulfonamide). Or you can do a nice methanolysis procedure using Me2NCH(OMe)2 in MeOH + NaOMe, the example was posted here on October 4 2006. (In the posted example the used amide was exceptionally hindered and unreactive – that’s why the methanolysis was done over 5 days – normally these alpha-amino subst piperidine amides require hydrolysis in refluxing glycol with KOH. In less hindered cases this system produces complete methanolysis within hours, often the methoxide is not even needed in less hindered cases, the DMF-DMA basicity and MeOH as a solvent suffices).

    Me-esters are usually easy to purify on a column – in this case an extra step can be worth the trouble.

    I dont have any experience with acyl chloride formation in the presence of sulfonamide but I don’t see any major complication. I would use the mildest conditions to be sure (oxaloyl chloride, 1.2-1.5 eq., 2 drops of DMF, DCM as a solvent, RT overnight)

    Comment by milkshake — September 21, 2008 @ 5:15 pm

  7. Hello MS,

    Many thanks for that. My compound is primary sulfonamide. Hope its stable under alkaline conditions. Sulfonamide is meta to the nitrile group and methyl group is in between the two groups..

    Thanks

    Marto

    Comment by Marto — September 22, 2008 @ 3:55 am


RSS feed for comments on this post. TrackBack URI

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

The Shocking Blue Green Theme. Blog at WordPress.com.

Follow

Get every new post delivered to your Inbox.

Join 138 other followers

%d bloggers like this: