[Kaladiscope]

Hi,

I am thinking about different strategies to synthesize one building block. I want to do the following reaction:

R-OMs + MgBrCF₂PO₃H₂  ----> R-CF-PO₃H₂

So, I would say that difluoro derivative attack the R (which is an alkyl chain) forming the corresponding C-C bond.

Do u think that is possible? or probably the R chain (alkyl) is not enough EWG to allow the reaction?

[g-bones]

That is an unusual nucleophile.  it contains a phosphoric acid type- moiety, which would not be tolerated under Grignard conditions (highly basic).  Also, Grigrards aren't very good for Sn2 Reactions.     

[nox]

I wonder whether a cross-coupling strategy could be employed here.

[discodermolide]

Even phosphonic acid esters -PO₃R'₂ are bad substrates for Grignards. The ester groups exchange with Grignard alkyl group and you end up with phosphine oxides.

[james_a]

Hi,

I am thinking about different strategies to synthesize one building block. I want to do the following reaction:

R-OMs + MgBrCF₂PO₃H₂  ----> R-CF-PO₃H₂

So, I would say that difluoro derivative attack the R (which is an alkyl chain) forming the corresponding C-C bond.

Do u think that is possible? or probably the R chain (alkyl) is not enough EWG to allow the reaction?

If you have access to a [protected] derivative of CHF2PO3H2, why not just try deprotonation with strong base and displacement of the mesylate, in a polar aprotic solvent such as DMF? Not sure if there will be preferential attack on the phosphorus, but perhaps worth a shot.

[orgopete]

This is chemistry I am unfamiliar with. In such a situation, this would be my normal operating procedure.

• I would first review as much chemistry as necessary to learn how RCF_nPO₃R₂ have been synthesized. The norm that I expect is the most productive chemistry will be repeated most frequently.
• I'd begin filtering through to try to find other strategies and how effective they are.  
• I'd begin to search for new reaction types, of which I'd consider this Grignard type reaction an example.

I presume the posted example is an hypothetical reaction as I would not expect a C-Mg bond to resist protonation by a phosphonic acid. None the less, even this can be a searchable item, a C-Mg and any OH bond together (I'm excluding examples where the OH becomes O-Mg by an excess of reagent). Then you can replace magnesium with other atoms, will these replacements catalyze the reaction you are attempting, etc.

This is what I suspect. Carbon-carbon bond formation can be done with a variety of ways and will give a lot of variety. Even so, if you are methodical, you can even write these as R(+), R•, and R(-) strategies and search for each. Eventually, I think this will fall into two different chemistry groups, fluorine and phosphonic acids. One of those chemistry categories will be the most compatible with your objective.

[discodermolide]

Hi,

I am thinking about different strategies to synthesize one building block. I want to do the following reaction:

R-OMs + MgBrCF₂PO₃H₂  ----> R-CF-PO₃H₂

So, I would say that difluoro derivative attack the R (which is an alkyl chain) forming the corresponding C-C bond.

Do u think that is possible? or probably the R chain (alkyl) is not enough EWG to allow the reaction?

If you have access to a [protected] derivative of CHF2PO3H2, why not just try deprotonation with strong base and displacement of the mesylate, in a polar aprotic solvent such as DMF? Not sure if there will be preferential attack on the phosphorus, but perhaps worth a shot.

Attack at the P atom depends of the esters. Obviously if it is a methyl attack is easy as compared to say isopropyl.
I am not even sure that such phosphonate species are known.

[Kaladiscope]

Here I found some literature about it:

http://www.mendeley.com/research/efficient-scaledup-synthesis-nfmoc4phosphonodifluoromethyllphenylalanine-incorporation-peptides/#page-1

J. Org. Chem., Vol. 61, No. 14, 1996

Such phosphate esters are comercially available:

For example one can use HCF₂PO(OEt)₂ and LDA as a strong base to then attack a carbonyl and generate the corresponding:

R-CH₂CH₂CHO + HCF₂PO(OEt)₂ ---> R-CH₂CH₂COH-CF2PO(OEt)₂

Or as alternative, just add Tf₂O to the alkyl alcohol and then nucleophilic displacement with LiCF₂PO(OEt)₂.

What I am just worried is about the stability of Fmoc-NH or carboxylic acid without protection against such conditions...