Palladium catalyst reactivity toward reaction conditions

A number of modified reaction conditions have been developed. One involves addition of silver salts, which activate the halide toward displacement.94 Use of sodium bicarbonate or sodium carbonate in the presence of a phase-transfer catalyst permits especially mild conditions to be used for many systems.95 Tetraalkylammonium salts often accelerate reaction.96 Solid-phase catalysts in which the palladium is complexed by polymer-bound phosphine groups have also been developed.97 Aryl chlorides are not very reactive under normal Heck reaction conditions, but reaction can be achieved by inclusion of triphenylphosphonium salts with Pd(OAc)2 or PdCl2 as the catalyst.98... 

Particular attention has been devoted to the catalytic activity of palladium (Pd /Pd ) salts, mostly because of their high reactivity in mild conditions. The reaction can be driven toward the formation of oxalate or carbonate (9-1J). The reoxidation of Pd° salts with oxygen can be easily performed in-situ if a suitable co-catalyst is used. Copper has been the most widely proposed. Unfortunately, the formation of water during the reoxidation process heavily interferes with the catalytic cycle. Therefore, non-conventional oxidants like peroxides (J2) or processes involving a separate reoxidation step have been proposed. A vapor phase two-step process based on palladium catalyzed carbonylation of methyl nitrite has been developed on an industrial scale in Japan (13). 

The reactivity of the chain-fluorinated halodiazines towards nucleophiles is to a considerable extent similar to that of the corresponding non-fluorinated analogues. In particular, chain-fluorinated 2(6)- and 4-halopyrimidines are the most reactive substrates for the nucleophilic attack, so that very mild reaction conditions are possible (Table 48, Entries 1, 6, 8). In the case of less reactive substrates, very harsh reaction conditions (e.g. heating or MW irradiation at 140-180 °C) still can promote classical nucleophilic substitution (Entries 9, 11, 13, 14, 16, 18), although using palladium or copper catalysts might be more convenient (Entries 10, 12). 

One modification to the established route involved a reversal in the order of the SnAt reaction and the Heck reaction. This change would be expected to improve the purge of palladium in the process by moving the palladium-catalyzed step earlier in the overall sequence. This process is shown in Scheme 7. Toward this end, a screen of Heck reaction catalysts was performed. While desired product 24 could be accessed via this approach, the Heck reaction was not efficient under any of the conditions examined, and many conditions provided mixtures of regioisomeric Heck products. Additionally, the chloropyrimidine 21 was found to be reactive (SnAt) with a variety of solvents and/or bases in the reaction screen. For these reasons, this sequence of transformations was not investigated further. 

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