ArOh Rocooch ArOch Roh C

Scheme 4.23 Methylation of phenols with mixed organic carbonates (ROCO2CH3).

As can be seen, asymmetrical carbonates give high chemoselective methylation reactions, provided that R has at least three carbon atoms (R > n-C3, entries 2-4). Yet, in the case of reactive benzyl or allyl termini, the O-alkylation (forming PhOR) competes significantly with the formation of anisoles (entries 5-6).

Most satisfactory results can be obtained with the use of 2-(2-methoxyethoxy) ethyl carbonate [CH3O(CH2)2O(CH2)2OCOOCH3 (MEC) entry 4], which allows O-methyl selectivity up to 99% for different phenols (Table 4.9).

"'These compounds can be easily obtained through the transesterification reaction of DMC with an alcohol ROH (see Ref. 38).

TABLE 4.8 Reactions of Phenol with Different Alkyl Methyl Carbonates"

TABLE 4.8 Reactions of Phenol with Different Alkyl Methyl Carbonates"

Entry

R =

Time (h)b

PhOCH3

PhOR

1

Et

15

90

10

2

n-Pr

17

95

5

3

n-Bu

15

97

3

4

CH3O(CH2)2O(CH2)2

20

>99

5

Bn

5

84

16

6

Allyl

21

83

17

aT = 120°C, phenol (3.3 mmol)/K2CO3,/3 = 1:1.1:5. DMF (30 mL). bTime for complete conversion of the substrate.

aT = 120°C, phenol (3.3 mmol)/K2CO3,/3 = 1:1.1:5. DMF (30 mL). bTime for complete conversion of the substrate.

TABLE 4.9 O-Methylation of Different Phenols by Methyl 2-(2-Methoxyethoxy)Ethyl Carbonate"

Entry

Ar

Conv. (%)

Yield (%)b

Purity (%)

1

Ph

100

81

>99

2

p-MePh

100

79

>99

3

2-Naphthyl

100

83

>99

aT = 140°C, substrate/K2CO3/MEC = 1:1.1:5. Triglyme (50 mL). ^Isolated yields of O-methylated derivatives.

aT = 140°C, substrate/K2CO3/MEC = 1:1.1:5. Triglyme (50 mL). ^Isolated yields of O-methylated derivatives.

More recently, the use of MEC was also reported by us in the methylation of primary aromatic amines (p-XC6H4NH2, X = H, Cl, NO2) and of ambident anilines such as those listed in Scheme 4.9.24-44 In the presence of a NaY faujasite and at atmospheric pressure, the reaction proceeds with a complete methyl che-moselectivity and even, most importantly, with a mono-N-methyl selectivity (9097%) comparable to that achievable with DMC. As for DMC, selectivity arises from the synergistic effect of the reactivity of the carbonate and the amphoteric properties of the zeolite. In that case, however, a preliminary kinetic investigation was performed using alkyl- and alkoxy-substituted anilines, and it provides some general conclusions.45a This analysis indicates that the reaction selectivity toward methylated anilines (ArNHMe) does not depend on the polarity of the reaction solvent (when used), while a key role is played by the size of the zeolite cavities. In fact, as the bulkiness of the substituents grows, selectivity drops, because the diffusion of bigger molecules into the cavities is increasingly difficult at the point where it becomes obviated. For instance, from aniline to p-butylaniline, selectivity decreases from 99% to 90% accompanied by a decreased conversion from 100% to 9% (at comparable reaction times). Even more impressive, is the drop with 3,5-di-t-butylaniline whose size cannot fit the zeolite pores, and yields a 82% selectivity with 9% conversion.

The reactivity of MEC with amino-phenols, -benzylalcohols, -acids, and -benzamides (substrates of Scheme 4.9) is largely modified by the properties of aromatic substituents (X = OH, CO2H, CH2OH, CONH2).44b Both steric and electronic effects on the reaction site (NH2 group) and the establishment of direct acid-base interactions between substituents X and the catalyst must be considered to explain the observed scheme of rate constants. Weakly acid groups (CH2OH, CONH2 up to OH: pKa of 16-17 up to 10) may help the adsorption over the NaY surface, and so favor the reaction. Aminobenzoic acids (pKa of 4-5), however, are the least reactive substrates, presumably because carboxylic groups go through strong acid-base interactions with the catalyst.

These results represent the first ever reported evidence of strict cooperation between the steric requisites of the faujasite catalyst and the reactivity of an asymmetrical carbonate, in simultaneously inducing high methyl chemoselectivity and mono-N-methylselectivity for primary amines.

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