Palladium catalysis phosphonation

Synthesis of isomeric chiral protected (63 )-6-amino-hexahydro-2,7-dioxopyrazolo[l,2- ]pyrazole-l-carboxylic acid 280 is shown in Scheme 36. Crude vinyl phosphonate 275, obtained by treatment of diethyl allyloxycarbonylmethyl-phosphonate with acetic anhydride and tetramethyl diaminomethane as a formaldehyde equivalent, was used in the Michael addition to chiral 4-(f-butoxycarbonylamino)pyrazolidin-3-one 272. The Michael addition is run in dichloro-methane followed by addition of f-butyl oxalyl chloride and 2 equiv of Huning s base in the same pot to provide 276 in 58% yield. The allyl ester is deprotected using palladium catalysis to give the corresponding acid 277, which is... 

Another instance for this linker class is the safety-catch linker by Lyttle, which was developed for the synthesis of nucleic acids on solid supports [62]. Starting from a resin carrying an Alloc-protected amino group fragment, conventional phosphoramidite chemistry was carried out to build up the desired immobilized nucleotide 57. Removal of the Alloc group via palladium catalysis under neutral conditions produces a polymer-bound intermediate 58 with a free amino functionality that can intramolecularly attack activated phosphonates and liberate the nucleotide 59 from the solid support (Scheme 16.14). More examples of safety-catch linkers that use the deprotection of an N-functionality as the activation step are listed in Table 16.1 (resins 61-65) [63-68]. 

An improved procedure has been developed for the preparation of vinylphos-phonate-linked dinucleotide analogues such as 226. The method involves the coupling of an H-phosphonate diester at 0-3 of the top nucleoside with a p-bromovinyl derivative of thymidine, using palladium catalysis. Optimization studies were carried out, and under the best conditions, yields were high. ... 

An additional advantage of Freeh s palladium pincer cross-couphng catalyst includes its well-defined fate after catalysis. Treatment of 10 with aqueous hydrochloric acid and thus under work-up conditions led to a rapid and complete catalyst degradation, accompanied by the formation of phosphonate, piperidinium salts, 1,3-diaminobenzene, and other insoluble paUadium-containing products, which were easily separable from the coupling products-an important issue to be considered in particular for pharmaceutical applications. All these advantages make, [ C H3-2,6-(NHP(piperidinyl)2)2 Pd(Cl)] (10) attractive for industrial applications. Indeed, 10 was successfully applied in industry, and nowadays is commercially available. 

Alk-2-enenitriles also result from the dehydrobromination of y-hromo-P-oxo-nitriles, alk-3-enenitriles from the palladium-catalysed reductive cleavage of 2-acyloxy-3-ethylenenitriles, 2-dimethylamino-alk-2-enenitriles from the reaction between aldehydes and diethyl 1-dimethylamino-l-cyanomethane-phosphonate under phase-transfer catalysis, 2-ureido-alk-2-enenitriles via... 

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