[Babcock_Hall]

Late last week I reacted (CH₃)₂NSO₂CH₃ with n-BuLi and then diethyl chlorophosphate.  We will purify next week, but there seems to be a little starting material and a new, slower-moving product.  I am cautiously optimistic. 

What surprised me was that the protocol used 1 equivalent each of the sulfonamide and chlorophosphate, and 1.1 equivalents of n-butyllithium.  They reported a yield of about 85%.  I have looked at a number of protocols for similar reactions, some of which were to produce sulfonyl phosphonates, and frequently only a half-equivalent of diethyl chlorophosphate is used.  I don't have references handy, but I will add them into this thread later.  When I discussed this some time ago, it was pointed out to me that the desired products (sulfonylphosphonate or sulfamidophosphonate) each have a more acidic hydrogen than the corresponding starting material, a sulfone or sulfonamide.

[rolnor]

Yes, the product can protonate the lithio-species half-way through the reaction. So you get low yield. 2eqv. N-Buli+2 eqv. Methylsulphone might fix this. Then you get the product in its de-protonated form. I think the de-protonated product is a poor nucleophile compared to the lithio-methyl sulphone. You could make a large excess of the lithio-methyl sulphone and ad the chlorophosphate to this. The slow-moving by-product is probably the double-phosphonated methyl sulphone. If you do this, use very short reaction time, the lithio-methyl sulphone can attack the phosphonate ester I imagine. The chloro phosphate is very reactive, one minute is enough I think.

[Babcock_Hall]

I have done a preliminary examination of the NMR data from two of the pools that I collected.  Both appear to be the desired product, in that the ratio of integrals in H-1 NMR is consistent with monophosphorylation of the anion.  The combined yield is 30%.  I am in the process of reviewing the literature of similar reactions again because we may need to perform this general reaction again soon.

[rolnor]

Can the slow-moving product be the hydrolyzed phosphonate, a mono-ester? Maybe you can check them again on TLC, can it be they are the same, but the slow-moming was in the salt-form? Anion? A little bit imaginative.

[Babcock_Hall]

The H-1 NMR integrals are inconsistent with that hypothesis.  Based on the corresponding process for sulfones, I would predict that adding the diethyl phosphonate group would increase polarity.  What was initially surprising is that the R_f values in the fractions were different from the R_f values of the crude product.  My hypothesis is that the crude product may have been overloaded on the TLC plate, which caused the discrepancy.  With the benefit of hindsight, we might have been able to save some time with a different solvent system.

[rolnor]

Its a very acidic compound and you have base present when loading the TLC-plate. Just dilute the sample with a small drop of HOAc and dry the spot carefully before developing the plate, it should be OK.

[rolnor]

I would limit the reaction-time, 1minute is more than enough. A chloro phosphate is very reactive. Longer reaction time can lead to by-products.

[Babcock_Hall]

I have been looking at various papers which perform the alkylation (usually of a methyl group) for sulfonamides or the related reaction for sufones.

Wrobel, Z. Tetrahedron (2001), 57(37), 7899-7907
The mole ratio of arylmethylsulfonamide to LDA to diethylchlorophosphate is 1:2:0.375.

El Hadri 1996
The mole ratio of N,N dimethylmethylsulfonamide to nBuLi to diethylchlorophosphate is 1:1.1:1.0.

Valente Bioorganic & Medicinal Chemistry Letters (2006), 16(15), 4115-4119
cyclic sulfonamide to LDA to diethyl chlorophosphate is 1:1.11:0.567

Toti Bioorganic & Medicinal Chemistry 21 (2013) 257–268.
(CH₃)HNSO₂CH₃ to nBuLi to diethyl chlorophosphate is 1:2:0.51
 
Ahlfors Patent
Methanesulfonylmoropholine to KHMDS to diethyl chlorophosphate is 1.0:0.86:0.57
 
Lee and Oh Synthetic Communications 1989 19(11-12):2209-2212.
For phenylmethylsulfone and related the mole ratio of sulfone, to BuLi to diethyl chlorophosphate is t 1:2.2:1. 

The only protocol that I have found so far in which the ratio of base to chlorophosphate was close to 1 to 1 is the paper by El Hadri and collaborators.  This is the procedure that I followed, and my yield was quite a bit less than theirs (roughly 85% vs. 30%).  I have enough material to proceed, but if we do similar reactions in the future, we may need to improve the yield.

The next sulfonamide will either be something we make or something that we buy in small quantities because of price.  It occurs to me that using ratios similar to Lee and Oh is an attractive idea.

[rolnor]

Yea, things can happen. Its hard to say whats going on, the product will be more acidic so this might be the problem?  The product protonates te lithio sulfonamide that is unreacted?? Maybe just use 2 eqv LDA?

[Babcock_Hall]

A few months ago we used lithium hexamethyldisilazane, LiHMDS, as the base to remove a proton from a methyl sulfonamide.  We used diethylchlorophosphate as the phosphorylating agent.  The reaction gave the desired product, and I am inclined to use it in preference to nBuLi.

[rolnor]

Great! Maybe there is a cool explanation why the LiHMDS is better to use

[Babcock_Hall]

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01523 
Granberg KL, J. Med Chem. 2019, 62, 3, 1385-1406. 

One thing that attracted me to this method is that the ratio of the methyl sulfonamide to base to the chlorophosphate is 1:2:1; in other words, there is not the approximate twofold of excess of the methyl sulfonamide over the phosphorylating agent that I found in most other protocols.  As to what is different, my speculation is that the steric bulk of this base prevents it from removing a proton from the product, which is more acidic than the starting material.

[rolnor]

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01523 
Granberg KL, J. Med Chem. 2019, 62, 3, 1385-1406. 

One thing that attracted me to this method is that the ratio of the methyl sulfonamide to base to the chlorophosphate is 1:2:1; in other words, there is not the approximate twofold of excess of the methyl sulfonamide over the phosphorylating agent that I found in most other protocols.  As to what is different, my speculation is that the steric bulk of this base prevents it from removing a proton from the product, which is more acidic than the starting material.

Or maybe the product becomes a TMS enol? I know that ethyl acetate is best lithiated by LiHMDS it gives better yields, better than LDA. Its interesting. I dont know if steric bulk stops deprotonation, maybe it does