A mild and chemoselective dealkylation of alkyl aryl ethers by cerium(III) chloride-NaI

Article abstract of DOI:10.1246/cl.2000.738

The alkoxy groups present ortho to carbonyl group in alkoxybenzaldehydes are selectively deprotected in high yields leaving other alkoxy groups unaffected by cerium(III) chloride-NaI in refluxing acetonitrile under neutral reaction conditions.

Full text of DOI:10.1246/cl.2000.738

738
Chemistry Letters 2000
A Mild and Chemoselective Dealkylation of Alkyl Aryl Ethers by Cerium(III) Chloride-NaI
J. S. Yadav,* B.V. Subba Reddy, Ch. Madan, and S. Riaz Hashim
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
(Received March 27, 2000; CL-000291)
The alkoxy groups present ortho to carbonyl group in
alkoxybenzaldehydes are selectively deprotected in high
yields leaving other alkoxy groups unaffected by cerium(III)
chloride–NaI in refluxing acetonitrile under neutral reaction
conditions.
groups intact. Such selectivity is a highly desirable feature in
the cleavage of ethers which offers various beneficial prospects
in organic synthesis. The cleavage was effected by cerium
chloride through the formation of a six-membered chelate ring.
Performing chemoselective transformations of polyfunc-
tional compounds is a challenging problem in organic synthe-
sis. Ethers are frequently used as stable protective groups for
the hydroxyl groups in multi-step synthesis of complex natural
products like polyketide derived macrolides and polyether
antibiotics.1 Among various ethers, methoxy ethers are the
most versatile2 owing to their ease of formation, inherent sta-
bility and a variety of available deprotection methods including
nucleophilic3,4 and Lewis acid promoted cleavages.5–7 In the
nucleophilic cleavage of aryl methyl ethers carrying electron
attracting groups, several competing reactions8 like dehalo-
genation via nucleophilic aromatic substitution, electrophilic
addition of formyl groups and Von Richter reaction by NaCN
in DMSO with nitro arylethers etc., are possible that limit the
efficiency of the methods. Furthermore reactive Lewis acids
such as aluminum and boron halides are found to offer no
selectivity and cleave all methoxy groups present in the sub-
strate. In addition, the nucleophilic cleavage of arylmethyl
ethers suffer from the use of strong basic conditions, require
long reaction times at elevated temperature, incompatibility
with other functional groups present in the substrate and the
use of highly polar solvents like DMF, HMPA and DMSO
which require tedious aqueous work-up. Although, the dealky-
lation of alkyl aryl ethers has been reported3 using MgI2·OEt2,
the procedure is applicable only to the 2,6-dimethoxy ben-
zaldehydes and that is not a general method for aldehydes hav-
ing various substituents like nitro, acetyl, benzoyl, benzyl,
prenyl and ester groups in the aromatic ring. In recent years,
lanthanide salts mediated organic reactions9 have attracted
much attention due to low toxicity, ease of handling, low cost
of the reagents, stability and recoverability from water.
However, the development of new methods with more effica-
cy, convenient procedures and better yields is of interest.
The cleavage requires longer reaction times when methoxy
groups are present either ortho to nitro or ester moieties in place
of carbonyl group. Further no cleavage was observed with
anisole and di or trimethoxy benzenes. The deprotection was
successful only with alkyl aryl ethers carrying formyl, acetyl and
ester groups in the aromatic ring. The protocol could be success-
fully applied for the selective removal of prenyl ethers present
ortho to nitro, formyl, acetyl and ester moieties in the molecule.
The deprotection of prenyl ethers occurs rapidly in high yields
within 2–4 h of reaction time when compared to arylmethyl
ethers. The reaction conditions are neither acidic nor basic and
afford demethylated products in good yields in reasonable reac-
tion times. The results summarized in Table 1 indicate the
scope of the reaction for various polymethoxy benzaldehydes.
The cleavage was also effected by 1 eq of anhydrous CeCl3 and
1 eq of NaI in acetonitrile resulting in dealkylated products
in comparable yields (68–90%). The reagent system
CeCl3·7H2O–NaI was selectively cleaved the alkoxy groups
located at ortho carbonyl group without affecting the methoxy,
prenyl, benzyl, acetyl, benzoyl and ester groups present in the
substrate.
In continuation of our work towards the total synthesis of
Lamellarin alkaloids, we required the chemoselective de-
methylation of polymethoxy benzaldehydes under mild condi-
tions. Since AlCl3 or BX3 in the chemoselective demethyla-
tion caused the removal of all methoxy groups present in the
substrate, herein we report a mild and efficient method for the
chemoselective cleavage of methoxy groups located at ortho to
carbonyl group leaving other methoxy groups unaffected by
cerium(III) chloride–NaI in acetonitrile (Scheme 1).
In conclusion, the letter describes the chemoselective
dealkylation of alkoxy groups present ortho to formyl, acetyl,
benzoyl, methoxycarbonyl and nitro groups in alkyl aryl ethers
by cerium(III) chloride–NaI in refluxing acetonitrile. The
method offers several advantages like mild reaction conditions,
simple experimental / isolation procedures, high chemoselectiv-
The combination of cerium(III) chloride and sodium iodide
in refluxing acetonitrile smoothly cleaved methoxy groups
located ortho to carbonyl group and leaving other methoxy
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
739
ity and compatibility with various functional groups hence it is
useful addition to the existing methods.
BVS thanks CSIR, New Delhi for the award of a fellow-
ship.
Reference and Notes
1
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10 Experimental : A mixture of methyl or prenyl ether (2
mmol), cerium(III) chloride heptahydrate (3 mmol), and
sodium iodide (3 mmol) in acetonitrile (10 mL) was stirred
under reflux for an appropriate time (Table 1). After com-
plete conversion as indicated by TLC, the reaction mixture
was diluted with water and extracted twice with ether (2 ×
15 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4 and concentrated in
vacuo. The resulting product was purified by column chro-
matography on silica gel (Aldrich, 100–200 mesh, ethyl
acetate–hexane, 2:8) to give the pure hydroxy compound.
1
2a (Table 1, Entry 1): mp 104–105 °C. H NMR (CDCl3):
δ 3.90 (s, 3H), 3.95 (s, 3H), 6.4 (s, 1H, Ar-H), 6.85 (s, 1H,
Ar-H), 9.8 (s, 1H, -CHO), 11.4 (s, OH). EI MS : m/z (%) :
182 (100), 167 (70), 139 (20), 111 (15).