4056
L. Zuo et al. / Tetrahedron Letters 49 (2008) 4054–4056
ment (0604071005 and 0704051005), the New Drug Basic
Research Program of the Shanghai Institute of Materia
Medica (07G603B005).
OH
O
OMe
CH3
O
iodocyclohexane
(10.0 equiv)
O
O
reflux, DMF, 14 h
91% yield
OH
OMe
CH3
2
References and notes
1
Scheme 2. Efficient demethylation of 5,7-dimethoxy-4-methylphthalide 1
by iodocyclohexane/DMF.
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Synthesis, 3rd ed.; Wiley-VCH: New York, 1999; p 249.
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9. Typical procedure for demethylation: 5,7-Dimethoxy-4-methylphthalide
1 (208 mg, 1.0 mmol) was dissolved in DMF (2.0 mL) in a round-
bottomed flask and iodocyclohexane (1.3 mL, 10.0 mmol) was added.
The reaction system was equipped with reflux condenser under argon.
The reaction mixture was refluxed for 14 h, cooled, poured into water
(20 mL) and extracted with EtOAc (20 mL Â 3). The organic layer was
washed with saturated aq NaHSO3 and brine, dried over Na2SO4 and
filtered. The filtrate was concentrated and dried in vacuum to afford
5,7-dihydroxy-4-methylphthalide (164 mg, 91% yield).
can be readily cleaved to afford clean phenol-derived prod-
ucts 4 in short reaction times (2.5–8 h) and in high yields.
The versatile by-products cyclohexene, and the remaining
HI and iodocyclohexane can be conveniently removed by
evaporation. A variety of functional groups including
OH (entry 1), COOH (entries 5 and 6) and lactone (Scheme
2) can be tolerated to the reaction conditions. It appears
that the electronic and steric effect has limited effect on
the process. The substrates bearing electron-donating
(entries 1–3), withdrawing (entries 4–6), a combination
(entry 7), and neutral (entry 8) groups can efficiently partic-
ipate in the reaction. The same trend is observed in terms of
steric effect (entries 2 and 6). We also demonstrated that the
protocol could be applied for fused aromatic systems
(entries 9–11). It is noteworthy that the substrates possess-
ing multiple methoxy groups can be removed at the same
time (entry 7). However, 10.0 equiv of iodocyclohexane is
required. The use of 5.0 equiv resulted in a mixture of
mono- and bis-demethylation product (entry 11).
Finally, we applied the method for the demethylation of
compound 1 (Scheme 2). Under the standard reaction con-
ditions, the two methyl groups could be cleanly removed
with 10.0 equiv of iodocyclohexane to give desired product
2 in 91% yield without further purification.9 Notably, the
method described here is more efficient than that of Cano-
nica et al. reported.7c,d
In summary, a new, efficient demethylation of aryl
methyl ethers using iodocyclohexane as HI source in
DMF has been developed. It has demonstrated that the
methyl group can be effectively removed in high yields
within short reaction times under relatively mild reaction
conditions. The strategy affords a new alternative approach
to the cleavage of methyl ethers, a widely used protecting
group for phenols.
Acknowledgments
We are grateful for financial support from National Sci-
ence Foundation of China (0801031005), Chinese National
Programs for High Technology Research and Develop-