Organic Process Research & Development 2009, 13, 647–651
A Simple and Efficient Process for the Preparation of 1,6-Dimethoxynaphthalene
Tianyong Zhang,* Qiusheng Yang, Huixian Shi, and Lifeng Chi
School of Chemical Engineering and Technology, Tianjin UniVersity, 92 Weijin Road, Nankai District, Tianjin 300072, China
Abstract:
methylation reagent, was seldom used in the large-scale
methylation but was used in the laboratory.12-14 In fact,
these methylation reagents have not been widely used in the
large-scale production of naphthalene ether derivatives including
1,6-DMN. Although DMS is toxic to humans and the environ-
ment (mainly due to formation of methanol and sulfuric acid
from its hydrolysis), its high activity, the mild reaction condi-
tions, simple postprocessing, and especially the low cost cause
its wider application in the industrial production of naphthalene
ether derivatives.15-19
There are many large-scale productions of naphthalene ether
derivatives using DMS as the methylation reagent in China.
According to the location of the methoxy groups on the two
naphthalene rings, dimethoxynaphthalenes exist as six isomers.
The dimethoxy difference in symmetry influences many pa-
rameters in their preparation such as purification, reaction time,
temperature, ratio of raw materials, etc. The industrial yield of
1,6-DMN (about 65%) was less than that of 1,7-DMN and 1,4-
DMN by the same industrial method used in China. The
mechanism of methylation of 1,6-DHN (1,6-dihydroxynaph-
thalene) with DMS is a typical SN2 reaction, in which a
naphthyloxy anion attacks at the carbon atoms of DMS.20,21 The
main reaction paths are given in Figure 1. The number of the
intermediates 2-8 depends on the alkali concentration, tem-
perature, solvents, and other factors. For economic reasons,
commercial aqueous NaOH solutions having concentrations
between 20-40% (w/w) are more preferably used, but the yield
of 1,6-DMN was only 80-85% (mol/mol) as shown in the
previous literature starting from cheap DMS and NaOH.22
Furthermore, a lot of wastewater was also made by using dilute
aqueous NaOH.23 Sometimes, instead of NaOH, alkali-metal
carbonate was used, producing much CO2. Solvents containing
much water overflowed and caused ineffective use of equip-
1,6-Dimethoxynaphthalene (1,6-DMN) was prepared by the
O-dimethylation of 1,6-dihydroxynaphthalene (1,6-DHN) with
dimethyl sulfate (DMS) in the presence of sodium hydroxide and
additives in different solvents. The main reaction determining
factors were divided into three categories with respect to yield and
purity of 1,6-DMN: (1) Type of solvents and adding methods of
NaOH had the highest effect on the results. (2) Amount of DMS
and concentration of NaOH were less important. (3) Reaction time
and temperature were the least important factors. The best
reductant was Na2S2O4, and it was only under N2 atmosphere
that yield and purity were also good. The improved process
provides more than 99% yield, which considerably reduces
the cost of 1,6-DMN, and more than 98% purity eliminates
the purification process in the follow-up industrial production.
1. Introduction
1,6-Dimethoxynaphthalene (1,6-DMN, also as 2,5-dimethoxy-
naphthalene) is an important fine chemical intermediate,1-4
which is a raw material for the synthesis of drugs, dyestuffs,
photographic materials, etc.5-7 For example, 1,6-DMN was used
to prepare 5-methoxy-2-tetralone, which is a pharmacophore
in the treatment of depression, schizophrenia, and Parkinson’s
disease.8,9 1,6-DMN is usually prepared with the Williamson
synthesis method, in which methylation reagents are methanol,
halomethane, or DMS (dimethyl sulfate). Methanol is a poor
methylation reagent and very low yields were achieved in the
methylation. Further study has been done to improve the yield
and purity of products with special catalysts such as solid acid
catalysts.10,11 For its high cost, iodomethane, the best active
* Corresponding author. Telephone: +0086-22-27406610. Fax: +0086-22-
27406610. E-mail: tyzhang@tju.edu.cn.
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10.1021/op800285t CCC: $40.75 2009 American Chemical Society
Published on Web 03/26/2009
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