New efficient method of alkoxymethyl etherification of secondary alcohols

Article abstract of DOI:10.1016/j.tetlet.2004.06.026

A new efficient method of MOM etherification of secondary alcohols using 2-(chloromethyl)-3,5-dioxahex-1-ene (Okahara's reagent) is reported.

Full text of DOI:10.1016/j.tetlet.2004.06.026

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5795–5797
New efficient method of alkoxymethyl etherification of
secondary alcohols
Yosuke Watanabe and Tetsuya Ikemoto*
Sumika Fine Chemicals Co. Ltd, 3-1-21, Utajima Nishiyodogawa-ku, Osaka 555-0021, Japan
Received 16 April 2004; revised 2 June 2004; accepted 4 June 2004
Abstract—A new efficient method of MOM etherification of secondary alcohols using 2-(chloromethyl)-3,5-dioxahex-1-ene
(Okahara’s reagent) is reported.
Ó 2004 Elsevier Ltd. All rights reserved.
Various kinds of hydroxyl protecting groups are known.
Of such groups, an alkoxymethoxy group is one of the
most widely used. For the production of the alkoxy-
methoxy group, however, there are generally known
only two methods.1 One of them includes addition of
alkoxymethyl chloride, which is highly toxic, to a small
excess of diisopropylethylamine. This method is not
necessarily a desirable one in view of the effects on the
health of the experimenter. The other method includes
an equilibrium reaction of alcohol with a large excess of
dialkoxymethane under strong acidic conditions. This
method cannot be used for compounds like b-hydroxy
esters because b-elimination will occur, nor can it be
used for compounds having functional groups unstable
under strong acidic conditions.
For secondary alcohols (entries 1–4), the corresponding
MOM ethers were obtained in good yield and in an
almost pure form without purification by distillation or
column chromatography. At first, because compound 2
had been reported to be obtainable by a reaction of 2-
benzyloxy-3-fluoro-1-propene with
a corresponding
alcohol (Eq. 2),3 we anticipated the same type of reac-
tion to mainly occur under acidic conditions. However,
when secondary alcohol was used, compound 3 was not
obtained but MOM ether 4 was obtained almost purely
upon elimination of chloroacetone. It is noteworthy
that, even in the case of b-hydroxy esters, this MOM
etherification proceeded without b-elimination (entry 3).
Even PPTS could catalyze this reaction, though a longer
reaction time was necessary than with the use of p-tolu-
enesulfonic acid.
We now report here a new type of formation of alk-
oxymethyl ether for secondary alcohols. We have found
that 2-(chloromethyl)-3,5-dioxahex-1-ene 1, which is
well known as a reagent for acetonylation,2 is also an
efficient reagent for MOM etherification especially of
secondary alcohols (Eq. 1). Table 1 shows the results
achieved by applying this alcohol-protecting method to
various alcohols.
When primary alcohol was used (entries 5–7), how-
ever, the corresponding MOM ether could not be
obtained in a pure form but was obtained as a mix-
ture. That is, compound 3 and some other byproducts
accompanied by acetal and ketal exchange reactions
were also obtained, though MOM ether 4 was mainly
obtained. Among primary alcohols, the bulkiness
OH
OCH2OMe
Acidic condition
+
Cl
Cl
O
OMe
ð1Þ
R1
R2
+
R1
R2
O
1
Keywords: MOM Etherification; Alkoxymethyl; Okahara’s reagent; Hydroxyl protecting groups.
* Corresponding author. E-mail: ikemoto@sumika-fine-chem.co.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.026

5796
Y. Watanabe, T. Ikemoto / Tetrahedron Letters 45 (2004) 5795–5797
Table 1. Novel MOM etherification under acidic condition
Entry
Alcohol
Catalyst
Reaction time (h)
Yield (%)a
1a
1b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
4
54
84
85
OH
OH
2a
2b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
2
40
84
86
COOMe
OH
OH
3a
3b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
2
32
94
95
Cl
COOEt
4a
4b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
2
60
94
98
OH
5a
5b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
2
24
51b
44b
6a
6b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
8
66
52b
59b
HO
HO
COOMe
COOMe
7a
7b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
6
45
59b
72b
OH
8a
8b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
12
88
55b
83b
9a
9b
p-TsOH (0.5 mol %)
PPTS (10 mol %)
36
212
55b
57b;c
OH
a Isolated yield.
b Purified by distillation or column chromatography.
c Starting material was recovered (30%).
F
Acidic condition
ROH
+
F
OBn
RO
OBn
ð2Þ
2
seems to have an effect on the yield of the MOM
ether.
however, when p-toluenesulfonic acid was used as a
catalyst, the yield was less than satisfactory because
byproducts were also produced.
These results are recognized as follows; that is, in the
case of secondary alcohol, an addition of the alcohol to
the 2-position of compound 1 (path A) scarcely occurs
due to the steric effect. Instead of that, an attack of the
alcohol on the acetal carbon and elimination of chlo-
roacetone (path B) occur, and MOM ether 4 would be
produced. On the other hand, in the case of primary
alcohols, addition of the alcohol to the 2-position of
compound 1, followed by complicated acetal and ketal
exchange reactions would also occur (Scheme 1).
The reactions proceeded as follows: To a mixture of
alcohol (12.5 mmol), 2-(chloromethyl)-3,5-dioxahex-1-
ene4 (15 mmol) and acetonitrile (12.5 mL) was added
p-toluenesulfonic
acid
monohydrate
(11.9 mg,
0.063 mmol) or pyridinium p-toluenesulfonate (314 mg,
1.25 mmol). The mixture was stirred at room tempera-
ture for 2–212 h. The reaction mixture was added to
saturated NaHCO3 solution (25 mL) and extracted with
EtOAc (25 mL). The extracted organic layer was washed
with saturated NaHCO3 solution (25 mL) and dried
over anhydrous MgSO4 (2.5 g). After filtration, the fil-
trate was concentrated under reduced pressure to give
the corresponding MOM ether. When primary alcohol
or tertiary alcohol (entries 5–9) was used, column
In the case of tertiary alcohols (entries 8 and 9), because
of the lack of the reactivity, long reaction time was
necessary. When PPTS was used as a catalyst, the cor-
responding MOM ether was almost the only product;

Y. Watanabe, T. Ikemoto / Tetrahedron Letters 45 (2004) 5795–5797
5797
Cl
Rb
Ra
H+
O
O
Cl
R
O
O
O
path A
Rc
Rd
3
O
O
+
ROH
Cl
O
O
H
path A
path B
O
R
path B
+
O
O
Cl
4
Scheme 1. Proposed reaction mechanism for MOM etherification.
chromatography or distillation was necessary to obtain
pure MOM ether.
Director of Central Research Laboratory, Sumika Fine
Chemicals Co., Ltd for his generous support of our
research.
We have hereby noted a possibility that 2-(chloro-
methyl)-3,5-dioxahex-1-ene may be a new efficient
reagent for MOM etherification. We are also studying
a new environmentally suitable method for synthesizing
2-(chloromethyl)-3,5-dioxahex-1-ene and will report the
outcome in the near future.
References and notes
1. For some reviews, see: Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, John Wiley: USA,
1999. 3rd ed.; Chapter 2.
2. (a) Gu, X.-P.; Ikeda, I.; Okahara, M. Bull. Chem. Soc. Jpn.
1987, 60, 397; (b) Gu, X.-P.; Nishida, N.; Ikeda, I.;
Okahara, M. J. Org. Chem. 1987, 52, 3192.
Acknowledgements
3. Mukaiyama, T.; Ohshima, M.; Nagaoka, H.; Murakami,
M. Chem. Lett. 1984, 615.
4. Purchased from Tokyo Kasei Kogyo Co., Ltd.
We thank Dr. Weiqui Wang for helpful discussions and
suggestions. We also thank Mr. Takeshi Watanabe,