Simple deprotection of acetal type protecting groups under neutral conditions

Article abstract of DOI:10.1016/j.tetlet.2004.08.035

Heating acetals with ethylene glycol causes the deprotection of acetal type protecting groups. When acetals such as MOM ethers, MEM ethers, and THP ethers were heated in ethylene glycol or propylene glycol, solvolysis proceeded smoothly to produce alcohols in excellent yield. This reaction is a very promising method for chemoselective deprotection of acetal type protecting groups.

Full text of DOI:10.1016/j.tetlet.2004.08.035

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7213–7215
Simple deprotection of acetal type protecting groups under
neutral conditions
Hideyoshi Miyake,* Takatsugu Tsumura and Mitsuru Sasaki
Department of Agriculture, Kobe University, Rokkodai, Nada-ku, Kobe 657-8501, Japan
Received 9 June 2004; revised 30 July 2004; accepted 9 August 2004
Abstract—When acetals such as MOM ethers, MEM ethers, and THP ethers were heated in ethylene glycol or propylene glycol,
solvolysis proceeded smoothly to produce alcohols in excellent yield. This reaction is a very promising method for chemoselective
deprotection of acetaltype protecting groups.
Ó 2004 Elsevier Ltd. All rights reserved.
R
R
R
OMOM
1
Selective protection and deprotection of hydroxyl
groups are very important procedures in multi-step syn-
theses of complicated molecules. Acetal type protecting
groups such as methoxymethyl(MOM), 2-methoxyeth-
oxymethyl(MEM), and tetrahydropyranyl(THP) are
commonly used for alcohols and phenols. Although
many methods to deprotect them have already been re-
ported,1 most were accomplished under acidic condi-
tions, which often causes adverse reactions. Recently,
Lee et al. are reported on the deprotection of MOM
and MEM protecting groups by reactions with CBr4
and i-PrOH.2 Seemingly, this reaction proceeded under
neutralconditions. However, HBr, generated from
CBr4 and i-PrOH in situ, causes deprotection. In this pa-
per, we report on a very simple method for the deprotec-
tion of acetaltype protecting groups under neutral
conditions.
R'
OH
OTHP
2
HO
R
OH
120 -160°C
4
OMEM
3
R' = H or Me
Scheme 1.
O
O
O
O
EG
HO
R
R
OH +
5
Scheme 2.
THP ethers, 2-(2-hydroxyethoxy)-1-oxacyclohexane
(5) was isolated (Scheme 2). For example, the deprotec-
tion of THP ether 2a and 2b gave 5 in 75% and
57% yield, respectively. Results are summarized in Table
1.
Our method is simple and inexpensive: heating acetals
with ethylene glycol (EG) or propylene glycol (PG)
(Scheme 1). The deprotection of acetals (1–3) proceeded
smoothly under these conditions to give alcohols (4) in
excellent yield. Not only MOM ethers (1) of alcohols
(primary, secondary, and tertiary), but phenols also re-
acted smoothly under similar conditions. The deprotec-
tion of THP ether (2) and MEM ether (3) also
proceeded. However, the deprotection of MEM ether re-
quired somewhat higher temperatures. In the case of
Although the deprotection of 1d and 3d proceeded with-
out destruction of ester groups, solvolysis of the ester
group of 1e occurred to some extent under the similar
conditions. The diastereoisomeric ratio of 1c did not
change during the deprotection. Both of the MOM
groups of 1f were removed in excellent yield in EG at
120°C.
Keywords: Deprotection; Acetal; Ethylene glycol; Propylene glycol.
*
However, in the case of 1g, a considerable amount of
alkenes was obtained (Scheme 3), probably because of
Corresponding author. Tel./fax: +81 78 803 5880; e-mail: miyakeh@
kobe-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.035

7214
H. Miyake et al. / Tetrahedron Letters 45 (2004) 7213–7215
Table 1. Deprotection of acetal-type protecting groups
Acetals
Conditions
Products
Yield (%)
92
1
EG, 140°C, 1h
Ph
4a
OH
Ph
1a
OMOM
4a
1a
2
3
1a
PG, 160°C, 25h
EG, 120°C, 1h
85
10
4a
92
Ph
2a
OTHP
Ph
Ph
4
5
EG, 140°C, 1h
94
OH
OMOM
Ph
4b
Ph
1b
Ph
EG, 140°C, 0.5h
4b
93
OTHP
Ph
2b
Ph
6
7
EG, 140°C, 5h
EG, 150°C, 1h
4b
96
86
OMEM
Ph
3b
Ph
Ph
OH
4c 90% de
OMOM
1c 90% de
8
9
EG, 120°C, 3h
EG, 140°C, 4h
92
96
MOMO
CH2COOMe
CH2COOMe
HO
CH2COOMe
1d
4d
4d
MEMO
3d
MeO
HO
78
10
COOMe
MeO
4e
MeO
MeO
10
EG, 120°C, 1h
MOMO
COOMe
1e
MeO
HO
COOH
4e'
MeO
OMOM
OMOM
OH
11
12
EG, 120°C, 1.3h
PG, 160°C, 6h
96
95
MOMO
HO
1f
4f0
O
O
OH
Ph
1g
O
Ph
4g
O
insufficient solubility of 1g to EG. To increase the solu-
bility of 1g, we used PG instead of EG, and the yield of
4g was successfully improved to 83%, recovering 13% of
1g.
retention of the configuration of the asymmetric carbon;
the enantiomeric excess was determined as benzoate.
Results are summarized in Scheme 5. The enantiomeric
ratio of (S)-3-phenyl-2-hydroxypropanoate did not
change during the course of protection, deprotection,
or benzoylation.
The chemoselective deprotection of the MOM group
in the presence of tert-butyldimethylsilyl (TBS) group
can be accomplished. The TBS group was not removed
under similar conditions. Results are summarized in
Scheme 4.
The plausible mechanism of these reactions is shown in
Scheme 6. Hydroxylgroups of the gylcolmake hydro-
gen bonds with oxygen atoms of acetals, and facilitate
the cleavage of the carbon–oxygen bond of acetals.
Then, a nucleophilic attack of a hydroxyl group of an-
other glycol cleaves from the carbon–oxygen bond to
The deprotection of the MOM ether of chiralmethyl
(S)-3-phenyl-2-hydroxypropanoate proceeded with

H. Miyake et al. / Tetrahedron Letters 45 (2004) 7213–7215
7215
Scheme 5.
Scheme 3.
MOMO
OH
HO
COOMe
6 +
°
160 C, 8.5 h
6%
TBSO
HO
6
HO
O
C
O
+
COOMe
TBSO
OH
TBSO
72%
6%
OH
HO
TBSO (CH ) OTHP
2 9
°
160 C, 22 h
7
Scheme 6.
TBSO (CH ) OH + 7
2 9
78%
18%
References and notes
Scheme 4.
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis 2, 3rd ed.; Wiley: New York, 1999; Recent
examples of the deprotection of acetals: Ranu, B. C.; Hajra,
A. J. Chem. Soc., Perkin Trans. 1 2001, 2262; Yu, C.; Liu,
B.; Hu, L. Tetrahedron Lett. 2000, 41, 819; Lee, A. S.-Y.;
Su, F.-Y.; Liao, Y.-C. Tetrahedron Lett. 1999, 40, 1323;
Lee, A. S.-Y.; Yeh, H.-C.; Shie, J.-J. Tetrahedron Lett.
1998, 39, 5249; Shibasaki, M.; Ishida, Y.; Okabe, N.
Tetrahedron Lett. 1985, 26, 2217.
give alcohols and acetal (route A). The alternative step-
wise deprotection route B is also plausible.
General procedures: About 10% solution of acetal (1–3)
in EG or PG was heated (conditions are summarized
in Table 1). After the usualworkup, the fool wing puri-
fication with column chromatography on silica gel gave
alcohol (or phenol) (4).
2. Lee, A. S.-Y.; Hu, Y.-J.; Chu, S.-F. Tetrahedron 2001, 57,
2121.