Org Prep Daily

October 2, 2006

3-hydroxy-5,5-dichloro-2,4-pentadienoic acid morpholide

Filed under: procedures — milkshake @ 7:46 pm

Diketene (Aldrich, stabilised with CuSO4) was distilled at reduced pressure (b.p. 70C/100Torr) to remove the stabilizer. Oven-dried glassware under stream of Ar was used because diketene and the intermediate tetrachloro beta lactone are moisture-sensitive. BocOOBoc was obtained from Boc2O (prep posted on Sept 7).

29.8g (354mmol) of freshly-distilled diketene was dissolved in carbon tetrachloride 250mL and BocO-OBoc (diBoc peroxide) 2.50g (10.67mmol, 3mol%) was added. This solution was transferred via canula into an addition funnel. Over the next 7 hours, this solution was added dropwise into vigorously-stirred carbon tetrachloride 80mL in a 0.5L flask that was kept on oil bath at 70C. (Under Ar-blanketed gas outlet. No condenser was necessary). After complete addition, the mixture was stirred at 70C for extra 90min. The mixture was cooled to R.T., additional BocOOBoc 0.835g (1 mol%) was added , the mixture was brought back to 70C and stirred for 90min at this temperature. (1H NMR indicated nearly complete conversion of diketene). The reaction mixture was then concentrated on rotavap and carefully dried on highvac. Y =77.85g (92%) of a pale-yellow oily liquid with a characteristic hydrocinnamaldehyde/rotten willow leaves-like odor. The purity of this crude product was approx 80% by 1H-NMR.

1H(CDCl3, 400MHz): 4.487(d, 17.3Hz, 1H), 3.977(d, 17.4Hz, 1H), 3.810(dAB, 15.9 Hz, 1H), 3.742(dAB, 15.9Hz, 1H) [impurity: 1.478 s + lots of baseline grass]

6.250g (26 mmol) of the crude tetrachlorobetalactone was dissolved in anh. dichloromethane (150mL) and the solution was cooled to 0C. Neat morpholine 2.40mL (27.5mmol) was added dropwise over 10 min. After additional 5 min, solid NaHCO3 powder 4.40g (52.3 mmol, 2 eq.) was added in a single portion, the cooling bath was removed and the mixture was stirred at RT for 22 hours. (one day). The reaction mixture was filtered through a 1.5 x 2 inch plug of silica, the silica was washed with ethyl acetate 300mL. The filtrates were evaporated and the obtained solid residue was re-crystallized from a mix of ethyl acetate 20mL and cyclohexane 80mL (RT, overnight). The precipitated product was collected by filtration, washed with hexane and dried on higvac. Y=3.507g (53.5%) of a white crystalline solid. (There was some more product left in the supernatants but I was lazy that night).

1H(d6-DMSO, 400Mhz): 14.981(s, 1H), 6.696(s, 1H), 5.820(s, 1H), 3.598(br m, 4H), 3.507(br m, 4H)

The signals of the keto tautomer are barely detectable in the d6-DMSO solution of morpholide. With the corresponding piperide analog, the keto/enol ratio is much higher, about 15:85. These enol compounds fail to give good proton spectra in CDCl3 (= broad blobs). The signals in DMSO are nice and sharp, except for the methylene protons next to the amide nitrogen .

The tetra-Cl-beta lactone could be distilled on Kugelrohr at or below 70C/0.05 Torr but the distillation is risky. Acidic impurities (for example from hydrolysis) catalyse a self-accelerated decomposition of the lactone. Since the crude intermediate works quite well and the enolamides produced in the following step are stable and crystalline, it is best to avoid distilling this unstable lactone. The lactone did not store well – within 2 month at RT it turned into a black foamy slush with HCl gas evolution.

11 Comments »

  1. I had thought that CCl4 is always an inert solvent used for radical type of reactions such as bromination via NBS. Is diBOC peroxide necessary as an initiator for this reaction? the resulting t-butyl radical might have a long half-life.

    Comment by MissingSnow — October 2, 2006 @ 9:47 pm

  2. I have seen these radical additions before – it is an ancient and ugly telomerisation reaction of CCl4 with alkenes – the trouble is that the reaction likes to make oligomer so one has to use pseudo-high-dilution conditions (adding the alkene slowly together with the initiator into a large excess of CCl4) . I think one of the industrial methods for large-scale manufacture of cinnamic acid (needed for phenylalanine for Aspartam) involved CCl4 radical addition to styrene, followed by hydrolysis.
    I guess tBuO radical does abstracts the chlorine from CCl4. The original procedure actually called for (4-trans-tBu-cyclohexyl-OCO2)2 as initiator – a stuff that has a huge molecular weight, is no longer commercially available and even its chloroformate precursor is unavailable. So I thought, this should work with BocOOBoc (which is a known compound except that the literature prep from Boc-ON sucks so I made it from Boc2O) – I tried it and it worked. I figured the guys who developed this nasty procedure must have tried dibenzoyl peroxide or AIBN so I did not bother. It would be interesting to try a more modern version – initiation with Et3B and oxygen at RT.

    Comment by milkshake — October 2, 2006 @ 10:12 pm

  3. And how are we supposed to get carbon tet these days …😉

    Comment by SJB — October 3, 2006 @ 4:22 am

  4. Uh… Aldrich (at least in the US)? I just got 2 L in yesterday…

    Comment by milo — October 3, 2006 @ 11:40 am

  5. Hmm, last I remember looking it was fairly heavily restricted (at least here in the UK), maybe things have lightened up a bit recently – can’t remember the last time I saw a procedure that *needed* it in the same way as this one does so haven’t looked recently.

    Comment by SJB — October 3, 2006 @ 2:25 pm

  6. I’m in california, which has horrible restrictions on certain things… but never any problems getting CCl4. If I order it from Fisher, I usually get it within the week.

    Comment by Ryan K. — October 3, 2006 @ 5:55 pm

  7. You are right, CCl4 from Acros is available from Fisher, no problem here in Florida but it is pricey. (Aldrich CCl4 is even more expensive). I asked why does it cost $120-200/L and they said it is the Freon tax.

    Comment by milkshake — October 3, 2006 @ 6:08 pm

  8. One can even add CCl4 across the double bond of styrene based on Kharasch reaction. Earlier Cu based catalysts were used. Now it is being overshadowed by Ru catalyst. This is the trend in academia.

    Comment by pasupathy — March 10, 2009 @ 1:25 am

  9. can you provide me with the patent or journal information for the industrial methods for large-scale manufacture of cinnamic acid using styrene. What is the initiator use. Is it benzoyl peroxide.

    Comment by pasupathy — March 10, 2009 @ 3:15 am

  10. sorry if I remember correctly it was some Czechoslovak process patent related to production of Aspartame and phenyl alanine – I don’t have the reference

    Comment by milkshake — March 10, 2009 @ 6:47 am

  11. thx man. appreciate it

    Comment by pasupathy — March 10, 2009 @ 11:08 pm


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

Blog at WordPress.com.

%d bloggers like this: