[Babcock_Hall]

Recently I attempted to make 2-amino-5-phosphonopentanoic acid from 5-phosphonopentanoic acid.  I followed a protocol for 4-phosphonobutanoic acid (Wasielewski and Antczak, Synthesis, 1981, p. 540).  The ratio of Br2 to 5-phosphonopentanoic acid to PCl3 was 1:1:0.057, and the reaction was done under reflux overnight with no solvent but with a small stir bar.  After the reaction is over, one adds water then ammonia solution.   This procedure has sometimes worked well in our hands in the past.

It seemed to me that the Br2 had a slight tendency to boil off, even though I used a reflux condenser.  Also, the mass of acid was about 0.3 grams, and therefore the volume of PCl3 was quite small, less than 10 µL.  I am not sure how well the reagents were mixed, inasmuch as the reaction did not really seem to be a liquid.  I seem to have recovered starting material (I will try to confirm this).  I was tempted to try the reaction again, possibly mixing the reagents with something like a mortar.  I was also considering increasing the amount of PCl3 slightly.  Does anyone have any other suggestions?

[nox]

I have no experience with this reaction myself, but I did find an Org Syn prep for it (different substrate): http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv4p0616

Seems like stoichiometry might be an issue? They use a 1:1.01:2 ratio of acid:PBr₃:Br₂ from the start, and add a bit more bromine after refluxing a bit. Also, any reason you're using PCl₃ instead of PBr₃? Not that I think it would matter, but just curious.

[discodermolide]

Recently I attempted to make 2-amino-5-phosphonopentanoic acid from 5-phosphonopentanoic acid.  I followed a protocol for 4-phosphonobutanoic acid (Wasielewski and Antczak, Synthesis, 1981, p. 540).  The ratio of Br2 to 5-phosphonopentanoic acid to PCl3 was 1:1:0.057, and the reaction was done under reflux overnight with no solvent but with a small stir bar.  After the reaction is over, one adds water then ammonia solution.   This procedure has sometimes worked well in our hands in the past.

It seemed to me that the Br2 had a slight tendency to boil off, even though I used a reflux condenser.  Also, the mass of acid was about 0.3 grams, and therefore the volume of PCl3 was quite small, less than 10 µL.  I am not sure how well the reagents were mixed, inasmuch as the reaction did not really seem to be a liquid.  I seem to have recovered starting material (I will try to confirm this).  I was tempted to try the reaction again, possibly mixing the reagents with something like a mortar.  I was also considering increasing the amount of PCl3 slightly.  Does anyone have any other suggestions?

Try doing this on a bit larger scale.
I would suggest that the PCl₃ and Br₂ evaporated and a reflux condenser will not hold it. Use PBr₃.
How do you intend to mix these reagents in a mortar? Just scale it up. You must be able to synthesize 5-phosphonopentanoic acid on a reasonable scale.

[Babcock_Hall]

I have no experience with this reaction myself, but I did find an Org Syn prep for it (different substrate): http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv4p0616

Seems like stoichiometry might be an issue? They use a 1:1.01:2 ratio of acid:PBr₃:Br₂ from the start, and add a bit more bromine after refluxing a bit. Also, any reason you're using PCl₃ instead of PBr₃? Not that I think it would matter, but just curious.

I used PCl3 because I was following the reference that I had closely.  However, I like the PBr3 idea, and I see nothing wrong with trying the higher mole ratio of PBr3 than PCl3.

[Babcock_Hall]

Recently I attempted to make 2-amino-5-phosphonopentanoic acid from 5-phosphonopentanoic acid.  I followed a protocol for 4-phosphonobutanoic acid (Wasielewski and Antczak, Synthesis, 1981, p. 540).  The ratio of Br2 to 5-phosphonopentanoic acid to PCl3 was 1:1:0.057, and the reaction was done under reflux overnight with no solvent but with a small stir bar.  After the reaction is over, one adds water then ammonia solution.   This procedure has sometimes worked well in our hands in the past.

It seemed to me that the Br2 had a slight tendency to boil off, even though I used a reflux condenser.  Also, the mass of acid was about 0.3 grams, and therefore the volume of PCl3 was quite small, less than 10 µL.  I am not sure how well the reagents were mixed, inasmuch as the reaction did not really seem to be a liquid.  I seem to have recovered starting material (I will try to confirm this).  I was tempted to try the reaction again, possibly mixing the reagents with something like a mortar.  I was also considering increasing the amount of PCl3 slightly.  Does anyone have any other suggestions?

Try doing this on a bit larger scale.
I would suggest that the PCl₃ and Br₂ evaporated and a reflux condenser will not hold it. Use PBr₃.
How do you intend to mix these reagents in a mortar? Just scale it up. You must be able to synthesize 5-phosphonopentanoic acid on a reasonable scale.

I was thinking of using a small plastic pestle and using the reaction flask as the mortar, but I don't really like that idea.  With a greater amount of PX3, perhaps I will actually have a solution, as opposed to something that seemed to have the consistency of sludge.  That may simplify any mixing problems I might have had.  The synthesis of the triester of 5-phosphonopentanoic acid via Michaelis-Arbuzov  chemistry often shows a slight impurity, but the removal of the ester groups is usually not too bad.  I should be able to increase the scale somewhat, at least threefold.

[Babcock_Hall]

Try doing this on a bit larger scale.
I would suggest that the PCl₃ and Br₂ evaporated and a reflux condenser will not hold it. Use PBr₃.
How do you intend to mix these reagents in a mortar? Just scale it up. You must be able to synthesize 5-phosphonopentanoic acid on a reasonable scale.

I wanted to address the problem of making pure 5-phosphonopentanoic acid.  When we did this in the past, we used Michaelis-Arbuzov chemistry with triethylphosphite to make an intermediate triester, which we deprotected in the final step.  We had a devil of a time getting the ester pure, probably because of isomerization of the starting material.  The free acid is purified by Dowex, which is fine on a modest scale, but the columns would become impractical on a large scale.  If I were to pursue this again, I might go with a Michaelis-Becker reaction.