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I'm trying to do a reaction with phenyl piperazine, triphosgene, and 4-bromophenol. However, every time I do this reaction I seem to get the carbonyl di-4-phenylpiperazine as a major product (based on the LCMS masses). I tried to reduce the triphosgene step to 5min, which seemed to yield trace amounts of the intended product, but I still can't get my intended product as the major product. This should be such a simple reaction - what am I doing wrong?

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  • $\begingroup$ Try reversing the order. First, add 1: 1 triphosgene to 4-bromophenol (with stronger base) and then add phenyl piperazine. $\endgroup$ Jul 12, 2019 at 23:44

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You are forming the urea because there is always an excess of phenylpiperazine present to react with the carbamoyl chloride you are forming. You need to add the phenylpiperazine to the triphosgene. The paper by Varjosaari et al. [1] has a procedure (described on Organic Chemistry Portal) that should work.

@Mathew Mahindaratne's suggestion will also work:

Try reversing the order. First, add 1: 1 triphosgene to 4-bromophenol (with stronger base) and then add phenyl piperazine.

References

  1. Varjosaari, S. E.; Suating, P.; Adler, M. J. One-Pot Synthesis of O-Aryl Carbamates. Synthesis 2016, 48 (01), 43–47. https://doi.org/10/gf4wh2.
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  • $\begingroup$ Ahh yes that makes sense. I’ll retry and report back! $\endgroup$ Jul 14, 2019 at 17:57
  • $\begingroup$ So I redid the reaction but did not use pyridine. I thought it was too messy for a reaction where high yield was not an issue. Instead, I started with triphosgene in DCM (same 1/3 eqv.), then added the piperidine diluted in DCM dropwise to it, all at -10C. I let that stir for a while and added catalytic DMAP, and then bromophenol dissolved in DCM with 2eqv of Et3N. I do see the product in the LCMS, but the yield is probably only around 20%. $\endgroup$ Jul 19, 2019 at 12:26
  • $\begingroup$ Did you have a base (Et3N or similar) mixed with the piperidine or in with the triphosgene? $\endgroup$
    – Waylander
    Jul 19, 2019 at 12:53
  • $\begingroup$ I used 2 eqv of triethylamine which I added to the bromophenol, I did so because I assumed the puperadine was nucleophic enough for the phosgenation. $\endgroup$ Jul 20, 2019 at 0:41
  • $\begingroup$ You need Et3N in with the piperazine. The reaction with triphosgene produces HCl which will protonate further piperazine as you add it so it will not react. $\endgroup$
    – Waylander
    Jul 20, 2019 at 7:12

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