Org Prep Daily

July 20, 2007

4-(5-Chloro-1,3-benzodioxolyl)-Isocyanate

Filed under: procedures — milkshake @ 4:34 am

isocyanate.gif

4-amino-5-chloro-1,3-benzodioxole 858 mg (5.00 mmol) was dissolved in toluene 20mL and 4M anh. HCl solution in dioxane 1.5mL (6 mmol) was added dropwise. The formed slurry was stirred vigorously for 10 min. Phosgene 20% solution in toluene 15 mL (Fluka, approx 1.9M solution; 28.5 mmol) was added to the mix, the flask was equipped with a Drierite-filled gas outlet tube and the mixture was stirred on oil bath at 70C for 45 min and then at 90C for additional 45 min. (The hydrochloride slurry gradually dissolved with gas evolution). The reaction mixture was cooled to RT, filtered (the fritted funnel was washed with toluene) and the filtrates were evaporated to dryness. The obtained solid residue was dissolved in cyclohexane 10mL with gentle heating, the solution was diluted with hexane 10 mL and allowed to crystallize at RT overnight. The first crop (large needles, 388mg) was obtained by decanting the supernatants and rinsing the precipitate briefly with pentane, then drying on highvac. Cooling the supernatants to -15C in a freezer overnight, a second pure fraction (465mg) crystallized.  Combined yield was 853mg (86%) of coarse light tan needles.

1H(CDCl3, 400MHz, ref. TMS): 6.867(d, 8.4Hz, 1H), 6.605(d, 8.4Hz, 1H), 6.047(s, 2H); 13C(CDCl3, 100MHz, ref TMS): 147.27, 142.41, 128.48(br s), 122.61, 121.92, 115.28(br s), 106.06, 102.63

4-amino-5-chloro-1,3-benzodioxole preparation was posted in Org Prep Daily on Sept 24 (2006)

Using the same procedure,  5-chloro-2,1,3-benzothiadiazol-4-yl isocyanate was prepared from 4-amino-5-chloro-2,1,3-benzothiadiazole (TCI-US) in 59% yield as pale yellow cotton-like fibrous needles (recryst from cyclohexane, to RT).

Note: There was a significant phosgene gas evolution from the heated reaction mixture and phosgene also condensed in the rotavap receiving flask. Using an efficient fume hood and cleaning the rotavap after the evaporation is a necessity: Unlike zombies, the sweet-smelling phosgene gas eats lungs without causing an immediate discomfort.

15 Comments »

  1. a friend of mine was using phosgene and said the bottle they used came with some badges that change color when they come into contact with phosgene. Know anything about them?

    Comment by excimer — July 20, 2007 @ 10:15 am

  2. Regarding the safety issues of phosgene, did you consider generating phosgene in situ from triphosgene? Or, is it preferable to work with a gas versus solid triphosgene in this case?

    Comment by Totally palytoxined out — July 20, 2007 @ 2:21 pm

  3. paly – milkshake’s procedure calls for the commercially available solution of phosgene in toluene. not to shill for Sigma-aldrich, but you can get it from them:

    http://www.sigmaaldrich.com/catalog/search/ProductDetail/FLUKA/79380

    when handled in the fume hood, it can be safely transfered by syringe for your needs. the same solution is used to prepare some of the less available (or more expensive) carbamate protecting group reagents (like Teoc-Cl) by reaction of phosgene with the appropriate alcohol (e.g. 2-trimethylsilyl-1-ethanol).

    Comment by cjdquest — July 20, 2007 @ 2:47 pm

  4. Ahhhh, my oversight. Thanks.

    I still know of a few folks who use phosgene gas out of the cylinder. Perhaps it reminds them of chemistry days of old?

    Comment by Totally palytoxined out — July 20, 2007 @ 6:31 pm

  5. The cassical procedure of making isocyanates from anilines calls for saturating the slurry of the aniline HCl salt in toluene with a stream of phosgene gas at RT. In my case the o,o’-disubst anilines were pretty unreactive so I had to heat them up a bit – and I could not use a huge excess of phosgene because the phosgene tank is hard to get nowadays and the commercial solution (Fluka) is I think truck-only material so it takes more than a week to get it here in Florida and it is not that cheap either.

    I would use diphosgene for things that really need to be heated high. Also one can crack triphosgene (I think this should work in situ too but the trouble here would be the low volatility of the unreacted reagent).

    Comment by milkshake — July 21, 2007 @ 2:30 am

  6. I made a ton of isocyanates from anilines using triphosgene and DCM as a post doc, most work like a charm…

    Comment by Milo — July 21, 2007 @ 9:37 pm

  7. What conditions- a reflux? Starting with free base or with hydrochloride? What ratio of reactants? I have to admit that this is the first time that I was making isocyanates from amines – I would usualy buy them.

    Comment by milkshake — July 22, 2007 @ 6:42 pm

  8. Holy cow, you used phosgene willingly? Isn’t it possible to use “safe” phosgene instead (Eg. Cl3COOCOCl3?

    Comment by Art — July 22, 2007 @ 7:47 pm

  9. I’ve made isocyantes at zero degrees from amines, triphosgene (0.4 equiv, or 1.2 phosgene equivalents), and triethyl amine (excess, especially if the amine is and HCL salt), in DCM. You can do an aqueous workup to rid yourself of the amine HCl, the isocyanate survives quite nicely.

    Zero degrees was for aliphatic and unhindered aniline amines. Maybe room temperature for hindered or electron deficient ones. Might have to heat and switch to dichloroethane for hindered and unreactive anilines, like with a nitro group on the ring.

    Comment by Tom — July 25, 2007 @ 10:50 am

  10. thank you!

    Comment by milkshake — July 25, 2007 @ 6:31 pm

  11. Anybody know how to neutralize methylisocyanate?

    Comment by pmgb — August 24, 2008 @ 6:53 pm

  12. I would use ammonia or methylamine. But if it is in a gas stream and you need to use some solid scrubber I would use “soda lime” granules – it is NaOH+Ca(OH)2 mixture that comes in chunks.

    Comment by milkshake — August 25, 2008 @ 1:32 am

  13. What is the purpose of making aniline HCL SALT before treating with Phosgene or its equivalents.

    Comment by Pashu — September 18, 2008 @ 6:19 am

  14. To supress the formation of N,N’diaryl ureas. The reaction could be too fast to control otherwise.

    Comment by milkshake — September 18, 2008 @ 1:24 pm

  15. Thx dude. appreciate that.

    Comment by Pashu — September 19, 2008 @ 1:22 am


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