Batch Methylation Reactions with DMC

Under batch conditions, methylations with DMC must necessarily be run in sealed autoclaves, given its boiling point (90°C) and the reaction temperature (>160°C). Batch methylations with DMC can be performed on a number of different substrates and, under such conditions, the reaction mechanism can be conveniently investigated: in fact, the sampling of the reaction mixture at different conversions, and the identification of possible intermediates (see later) is easier with respect to CF-processes. For compounds that are susceptible to multiple methylation, the results are of special interest, since methylation with DMC totally inhibits multiple substitution in both N- and C-alkylation, for primary aromatic amines and for CH2-active compounds, respectively.

The most interesting and best-studied reaction, particularly in view of its selectivity, is the mono-C-methylation of arylacetonitriles (Scheme 4.6).

In the presence of a weak base (usually K2CO3), these compounds can be

Scheme 4.6 Mono-C-methylation of arylacetonitriles (X = CN).

Scheme 4.6 Mono-C-methylation of arylacetonitriles (X = CN).

effectively mono-C-methylated with an unprecedented selectivity—greater than 99%—at complete conversions. For instance, when a mixture of PhCH2CN, DMC, and K2CO3 in a 1:20:2 molar ratio, respectively, was allowed to react at 180°C for 3.75 h, 2-phenylpropionitrile was obtained in a 95% yield with a purity >99%.19 For comparison, in the same reaction run under PTC conditions and using CH3I, the mono- to dimethyl-derivative ratio never exceeded 2.4.20 The very high monomethyl selectivity has turned out to be much interesting for the synthesis of precursors for anti-inflammatory drugs: some examples are listed in Table 4.5.

Similarly, in the presence of weak inorganic bases (K2CO3), the reactions of DMC with sulfones bearing a-methylenic groups (RCH2SO2R'; R = Alkyl, Aryl; R' = Aryl) afford the respective mono-C-methylated compounds [RCH(CH3)SO2R'] with >99% selectivity at complete conversions (Scheme 4.7).21

TABLE 4.5 Mono-C-Methylation of Arylacetonitriles

Conv.

Selectivity in Mono-

Intermediate

X

Ar

(%)

C-Methylation

for

CN

4-Isobutylphenyl

99

99

Ibuprofen

CN

3-Carboxymethylphenyl

100

>99

Ketoprofen

cooch3

2-(6-Methoxynaphtyl)

100

>99

Naproxen

Conditions: Autoclave, substrate:DMC:K2CO3 = 1:18:2 molar ratio, T = 180-220°C.

Conditions: Autoclave, substrate:DMC:K2CO3 = 1:18:2 molar ratio, T = 180-220°C.

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Responses

  • Iole
    Why are methylation reactions interesting?
    9 years ago

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