A practical synthesis of 2-bromo-6-methoxynaphthalene

Full text of DOI:10.1080/00304940903526986

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Organic Preparations and Procedures
International: The New Journal for
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A Practical Synthesis of 2-Bromo-6-
methoxynaphthalene
Wei-Ming Xu a & Hong-Qiang He a
a College of Material Chemistry and Chemical Engineering ,
Hangzhou Normal University (Xiasha Campus) , Hangzhou, P. R.
China
Published online: 03 Feb 2010.
To cite this article: Wei-Ming Xu & Hong-Qiang He (2010) A Practical Synthesis of 2-Bromo-6-
methoxynaphthalene, Organic Preparations and Procedures International: The New Journal for
Organic Synthesis, 42:1, 107-109, DOI: 10.1080/00304940903526986
To link to this article: http://dx.doi.org/10.1080/00304940903526986
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Organic Preparations and Procedures International, 42:107–109, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903526986
OPPI BRIEFS
A Practical Synthesis
of 2-Bromo-6-methoxynaphthalene
Wei-Ming Xu and Hong-Qiang He
College of Material Chemistry and Chemical Engineering, Hangzhou Normal
University (Xiasha Campus) Hangzhou, P. R. China
2-Bromo-6-methoxynaphthalene (2) is an important intermediate in the preparation of
non-steroidal anti-inflammatory agents,1,2 such as 4-(6-methoxy-2-naphthyl)- 2-butanone
(nabumetone) and 2-(6-methoxy-2-naphthyl)propionic acid (naproxen). A survey of the
literature indicates that several synthetic procedures1–8 already exist. Among them, methy-
lation of 6-bromo-2-naphthol (1) to give 2-bromo-6-methoxynaphthalene (2) with dimethyl
sulfate2,3 and methyl halides4–6 are most commonly used. Methyl chloride5 and methyl
bromide6 are gases at room temperature and thus have a limited utility. However, other
reagents (dimethyl sulfate and methyl iodide) present serious toxicological and carcino-
genic risks due to their volatility and their ability to methylate nucleic acids in living
organisms.
Environmental and toxicological concerns have resulted in increased interest in new
methylating reagents. As a consequence, Maras et al.7 developed an efficient synthesis of
2-bromo-6-methoxynaphthalene (2) using tetramethylammonium chloride as a methylating
agent, but the reaction was carried out under microwave-assisted conditions. Alternatively,
Raju et al.8 reported a site-directed nuclear bromination by two-phase electrolysis of 2-
methoxynaphthalene and sodium bromide to obtain 2. The high yield accompanied with
high regioselectivity of the electrochemical method might prove promising for future in-
dustrial use.
Recently, dialkyl carbonate and in particular dimethyl carbonate (DMC) was used
as an environmentally benign substitute for methyl halides and dimethyl sulfate.9 Carbon
dioxide and methanol, which can be easily removed from the reaction medium, are the only
by-products formed.
Submitted August 28, 2009
Address correspondence to Wei-Ming Xu, College of Material Chemistry and Chemical En-
gineering, Hangzhou Normal University (Xiasha Campus)Hangzhou, 310036, P. R. China. E-mail:
wmxu@zju.edu.cn
107

108
Xu and He
As a continuation of our interest in the study of medicinal compounds,10–11 we
have developed a practical pilot-scale method for the preparation of 2-bromo- 6-
methoxynaphthalene (2) from DMC and 6-bromo-2-naphthol (1) (Scheme 1); the latter
was easily prepared by a previous reported two-step bromination of 2-naphthol.1,3,6
Scheme 1
It is noteworthy that in this process only catalytic amount of base and no additional
solvent were used.
Experimental Section
Mps and bps are uncorrected. The purity of products was established on an Agilent 1100
HPLC. 1H NMR spectra were recorded in CDCl3 on a Bruker 400 (400 MHz) instrument
with TMS as internal standard. All chemicals were reagent grade and available commer-
cially. The elemental analysis was performed on a Flash EA1112 instrument.
2-Bromo-6-methoxynaphthalene (2)
In a 100 mL round-bottomed flask, fitted with a mechanical stirrer, an addition funnel, and a
reflux condenser fitted with a calcium chloride drying tube, was placed 22.3 g (0.10 mol) of
6-bromo-2-naphthol (1), 2.76 g (0.02 mol) of potassium carbonate and 2.78 g (0.01 mol) of
tetrabutylammonium chloride. The temperature was raised to 135◦C (oil bath) and dimethyl
carbonate 9.9 g (0.11 mol) was added dropwise over 6 h while the temperature was kept
between 130–135◦C. Then the mixture was distilled to expel excess dimethyl carbonate
and formed methanol, then cooled to room temperature. The residue was dissolved in 140
mL of ethanol and filtered. The filtrate was concentrated to 60 mL, cooled to 5◦C and the
precipitated crystals collected and dried in vacuo to afford 22.4 g (95%) of the product (2)
as a pale-yellow solid (HPLC >98.5%). 1H NMR (CDCl3): δ3.89 (3 H, s), 7.07 (1 H, d, J
= 2.8 Hz), 7.14 (1 H, dd, J = 2.8, 9.2 Hz), 7.48 (1 H, dd, J = 2.0, 8.8 Hz), 7.58 (1 H, d, J =
8.8 Hz), 7.62 (1 H, d, J = 8.8 Hz), 7.89 (1 H, d, J = 1.6 Hz). 13C NMR (CDCl3): δ 157.9,
133.0, 130.0, 129.6, 129.5, 128.5, 128.3, 119.7, 117.0, 105.7, 55.3. An analytical sample
was prepared by recrystallization from ethanol, mp. 102.5–103.5◦C, lit.1 mp. 102.5–104◦C.
Anal. Calcd. for C11H9BrO: C, 55.72; H, 3.83. Found: C, 55.58; H, 3.89.
Acknowledgment
We thank the National Natural Science Foundation of China (Grant No. 20602029) and
Hangzhou Normal University for support of our research.

Practical Synthesis of 2-Bromo-6-methoxynaphthalene
109
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