x ch3

Scheme 4.11 Demethoxycarbonylation (k2) vs. methylation (k5) for CH2-active compounds.

reveals that both the starting reagent 2a and its methyl derivative 1a undergo demethoxycarbonylation reactions at comparable rates while the methylation step of the intermediate 4a is the fastest reaction. In particular, at 140C, the pseudo-first-order rate constants of steps 6, 5, and the reverse of 2, namely, kg, k5, and k2, of Scheme 4.8, are 2.9103, 7.9103, and 2.7103 min1.*

Overall, the comparison of the kinetic behavior of the investigated steps reveals that the nonequilibrium methylation reaction is crucial in driving the overall process to completion. In fact, the higher rate of step 5 allows both the rapid consumption of 3a and the accumulation of 4a, which serves as a reactant for step 6. In other words, both equilibria 2 and 6 are regulated by irreversible reaction 5. The mechanism shows the key action of the methoxycarbonyl group, which by increasing the acidity of 3, acts as a promoter, significantly accelerating step 5.

At a high temperature, it is known that the lack of solvation may favor a Bai2 mechanism with respect a BAc2 one.26 In the case of DMC-mediated methyla-tions, both reaction pathways occur in a definite sequence, which accounts for the high monomethyl selectivity observed in these reactions.

Finally, it should be noted that esters and nitriles in the demethoxycarbonylat-ing step behave in a manner opposite to that in the methylating step. For nitriles, the methylation rate predominates over methoxycarbonylation; for esters, demethoxycarbonylation predominates (Scheme 4.11).

In order to clarify the different behavior of anion 2_ and 3_ (Scheme 4.10) toward DMC, various anions with different soft/hard character (aliphatic and aromatic amines, alcohoxydes, phenoxides, thiolates) were compared with regard to nucleophilic substitutions on DMC, using different reaction conditions.27 Results were in good agreement with the hard-soft acid-base (HSAB) theory.28 Accordingly, the high selectivity of monomethylation of CH2 acidic compounds and primary aromatic amines with DMC can be explained by two different subsequent reactions, which are due to the double electrophilic character of DMC. The first

*DMC is used in large excess. (200 equiv. with respect to the substrate). Therefore, its concentration is assumed to be constant throughout the reaction.

3 o O mechanism J J

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