Technology Report
A Continuous Methylation of Phenols and N,H‑Heteroaromatic
Compounds with Dimethyl Carbonate
Ulf Tilstam*
CMC Solutions bvba, Overhemstraat 3, B-3320 Hoegaarden, Belgium
ABSTRACT: The methylation of phenolic substrates has been reevaluated using sulfolane as solvent instead of DMF. The
change of solvent gave in all cases cleaner production of the anisole products in very good yields. The reaction requires 0.1 equiv
of DBU, 2−3 equiv of DMC, and 2−5 vols of sulfolane depending on the substrate. At 220 °C the reaction time is 10 min.
Sulfolane is completely stable under the reaction conditions, excluding unwanted impurities from the solvent. The reaction could
also be extended to NH-indole and NH-imidazole derivatives utilizing 0.1 equiv of DBU and 2−3 equiv of DMC in 2 vols of
sulfolane. All NH-heteroaromatic compounds gave clean N-methylation.
evaluated for the N-methylation of 3-indolylacetonitrile to
compare the N- and C-alkylation of an activated methylene
compound. If potassium carbonate was replaced with
tetrabutylammonium bromide, the N-selectivity went up to
93:2.5 in comparison to 89:8 with potassium carbonate.
Ouk et al. reported an N-methylation of nitrogen-containing
heterocycles with DMC.9 The authors found that imidazole was
N-methylated in a selective reaction within a distillation setup
at 170 °C. Other heterocycles such as 1,2 pyrazole, mono- and
dimethylated pyrazoles, and pyrrole could be N-methylated
with this procedure although in low to good yields (60−90%).
Zhao et al. reported an N-methylation procedure with DMC
catalyzed by TMEDA.10 The reaction was performed in a
mixture of DMC and DMF with a catalytic amount of TMEDA
in the case of indole (10 mol %) at 95 °C for 8 h. Also other
NH-heterocycles and secondary amines were N-methylated
using this method. The reaction was performed with
phthalimide, benzotriazole, carbazole, 10H-phenothiazine, 1-
benzoylpiperazine, and benzoimidazole in yields between 60
and 90%.
Quaranta et al. reported the N-methoxycarbonylation and
the N-methylation of pyrrole with DMC with (tert-butylimino-
tris(dimethylamino)phosporane (P1-t-Bu) or tert-butylimino-
tris(pyrrolidino)-phosphorane (BTPP) catalysis.11 The authors
commented that with the phosphazenes as well as with DBU
the only reaction at room temperature is the carbamation
reaction. At higher temperatures and higher loadings of the
phosphazene the main pathway is the N-methylation of pyrrole.
At 150 °C, in the presence of 10 mol % of BTPP, pyrrole can
be quantitavely methylated with DMC to 1-methylpyrrole
within 3 h.
INTRODUCTION
■
Methylation is an important transformation that regularly
employs toxic and hazardous reagents such as methyl iodide1 or
dimethyl sulfate.2 The use of alternative reagents has been
scarce due to the harsh conditions required with dimethylcar-
bonate or methanol as methylating agents. Conditions reported
herein are often gas phase reactions with low molecular weight
substrates, but for large complex molecules this is not an option
for N- or O-methylation. Recently dimethyl carbonate (DMC)
as a methylating reagent for phenols and NH-containing
heteroaromatic compounds has been reported in conjunction
with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) under conven-
tional thermal heating with long reaction times. These authors
found that the change from conventional convection heating to
microwave energy increases the speed of the reaction.3 Rajabi
and Saidi reported a methylation of phenols and carboxylic
acids using microwave energy in a commercial microwave oven
without temperature control. They used DBU as base but in a
catalytic amount.4
Methylation of phenolic compounds is an industrially
important chemical process.5 Anisoles are widely utilized in
different industrial branches. They find major applications as
antioxidants in oils and grease manufacture, as stabilizers for
plastics, and as starting materials in the production of
agrochemicals and dyes.6
Nitrogen-containing heterocycles, such as indoles, imida-
zoles, pyrroles, and lately, indazoles, are ubiquitous building
blocks for the pharmaceutical chemistry. The N-methylation of
such heterocycles is commonly accomplished using toxic
reagents in the presence of a strong base.
The use of DMC for the N-alkylation of indole derivatives
with DABCO catalysis has been reported. The reaction is
performed in a mixture of DMC and N,N-dimethylformamide
(DMF) under reflux conditions in a batch reactor for 5−24 h.7
The authors also reported the methylation of indole-2-
carboxylic acid to furnish the corresponding N-methylindole-
2-carboxylic-methyl ester.
The use of DMC with potassium carbonate in refluxing DMF
for the selective N-methylation of indoles has also been
reported.8 The method gave the N-methylated indoles in high
yields. No C-alkylation was reported. The method was also
The methylation of electron-deficient pyrrole derivatives with
DMC has also been reported by Magnus et al.12 The authors
found that electron-deficient pyrroles can be methylated with
an excess of DMC and a small amount of DMF under DABCO
catalysis (10 mol %) at 90−95 °C after 23 h reaction time.
Received: July 28, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/op3002068 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX