Pyridones, Mitsunobu reaction

Pyridone is O-alkylated more readily than normal amides, because the resulting products are aromatic. With soft electrophiles, however, clean N-alkylations can be performed (Scheme 1.7). The Mitsunobu reaction, on the other hand, leads either to mixtures of N- and O-alkylated products or to O-alkylation exclusively, probably because of the hard, carbocation-like character of the intermediate alkoxyphosphonium cations. Electrophilic rhodium carbene complexes also preferentially alkylate the oxygen atom of 2-pyridone or other lactams [20] (Scheme 1.7). 

Like pyridones, oxy-diazines are readily deprotonated under mild conditions, to give ambident anions which can be alkylated conveniently by phase-transfer methods, alkylation usually occurring at nitrogen. " M-Arylations of uracils also proceed in this way with, for example, l-fluoro-4-nitrobenzene."" 3-Pyridazinones alkylate cleanly on N-2 under phase-transfer conditions," but the regiochemistry of uracil alkylation is sometimes difficult to control (see also below). Uracils are sufficiently acidic to take part in Mitsunobu reactions." ... 

In some reactions, there may be more than one possible reaction site. Typical Mitsunobu reaction partners in such reactions include pyridones, sulfahydantoins, etc. A few examples are shown below. Quinoline 254 was prepared from the corresponding pyridone in good yield reduction of the nitro group to the aniline was followed by condensation with another quinoline derivative to prepare quinoline based oligomers that form helical frameworks. ... 

Additional examples of ambident Mitsunobu reaction partners are shown in the figure below. Pyridones (255) frequently alkylate at the oxygen... 

The effect of substituents at the 3- and 5-positions of 2-pyridones on the attack at oxygen or nitrogen (the N/0 ratio) by ethyl lactate in the Mitsunobu reaction has been determined by product studies. Substituents at the 3-position do not affect the O/N ratio which is always near 1.0, significantly, while those at the 5-position have a marked effect on the O/N ratio. In fact, the O/N ratio varies from 5.75 when the substituent is MeO-to 0.74 when the substituent is CF3-. The O/N ratios for substituents on C(5) correlate with the substituent s Hammett R (Resonance Constant) value. 

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