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Sulfamidophosphonate synthesis via n-butyllithium: ratio of starting materials

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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.

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