An efficient protocol for the preparation of MOM ethers and their deprotection using zirconium(IV) chloride

Article abstract of DOI:10.1016/j.tetlet.2004.10.091

An efficient protocol for the preparation of MOM ethers from alcohols and formaldehyde dimethyl acetal (DMFA) using ZrCl₄ (10 mol %) at room temperature under solvent free conditions has been developed. Similarly, the same Lewis acid, ZrCl₄ (50 mol %), in isopropanol at reflux was utilised for the deprotection of MOM ethers. An efficient protocol for the preparation of MOM ethers from alcohols and formaldehyde dimethyl acetal (DMFA) using ZrCl₄ (10 mol %) at room temperature under solvent free conditions has been developed. Similarly, the same Lewis acid, ZrCl₄ (50 mol %), in isopropanol at reflux was utilised for the deprotection of MOM ethers.

Full text of DOI:10.1016/j.tetlet.2004.10.091

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9229–9232
An efficient protocol for the preparation of MOM ethers and
their deprotection using zirconium(IV) chlorideq
G. V. M. Sharma,* K. Laxma Reddy, P. Sree Lakshmi and Palakodety Radha Krishna
D-211, Discovery Laboratory, Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 9 August 2004; revised 4 October 2004; accepted 14 October 2004
Abstract—An efficient protocol for the preparation of MOM ethers from alcohols and formaldehyde dimethyl acetal (DMFA) using
ZrCl4 (10mol%) at room temperature under solvent free conditions has been developed. Similarly, the same Lewis acid, ZrCl4
(50mol%), in isopropanol at reflux was utilised for the deprotection of MOM ethers.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
lyst,22 NaHSO4ÆSiO2,23 and I2/MeOH.24 In view of the
drawbacks associated with the known methods such as
the need for stoichiometric amounts of expensive re-
agents, high temperatures, strong protic acid conditions,
slow reactions and tedious workup procedures, there is
a need to develop better reagents and conditions for
the preparation and deprotection of MOM ethers. Our
continued interest in the synthesis of new saccharides,
natural products25 from monosaccharides and synthetic
methods,25 prompted us to investigate a new procedure
for MOM protection and deprotection. Herein, we re-
port a simple and efficient ZrCl4 (10mol%) catalysed
method for MOM protection (at room temperature
under solvent free conditions) of alcohols in the presence
of a variety of acid sensitive groups and on substrates
such as carbohydrates, terpenes and others and the
deprotection of MOM ethers in isopropanol at reflux
(see Eq. 1).
Functional group protection and deprotection plays a
prominent role in the synthesis of complex natural prod-
ucts,1 while the selective removal of a protecting group is
an important topic in synthetic chemistry. Alcohols are
most commonly protected as ethers and esters, wherein
alkyl and benzyl ethers are permanent protective groups
(difficult to remove) while others, like THP, TBS, TPS
and MEM/MOM ethers are acid labile (easier to re-
move). Of the acetal derived protecting groups for
alcohols, such as THP and MOM/MEM, THP ethers
generate diastereomers upon protection, while such
problems do not arise with MOM and MEM groups.
MOM ethers are commonly prepared by alkylation of
the corresponding alkoxide anions with the highly carcin-
ogenic MOMCl.2,3 Alternatively, a variety of acidic rea-
gents such as P2O5,4 PTSA,5 Nafion-H,6 TMSI,7
molybdenum(IV) acetyl acetonate,8 BF3ÆEt2O,9 Enviro-
cat,10 sulfated zirconia,11 expansive graphite,12 FeCl3
dispersed on 3A molecular sieves13 and Sc(OTf)3,14 have
˚
ZrCl4 (10 mol%),
DMFA, rt
been reported for the preparation of MOM ethers using
formaldehyde dimethyl acetal (DMFA) and a new re-
agent, MOM-ON.15 Similarly, several methods were re-
ported earlier for the cleavage of MOM ethers, for
example, using HCl,16 BBr3,17 p-TsOH,18 ZnBr2,19
TiCl4,19 Me2BBr,20a (i-Pr)2BBr,20b CBr4,21 a clay cata-
R-OH
R-OMOM
ð1Þ
ZrCl4 (50 mol%),
isopropanol, reflux
2. Preparation of MOM ethers using ZrCl4 (10mol%)
Keywords: MOM ethers; Formaldehyde dimethyl acetal; Zirconium
chloride.
q IICT Communication No. 0407017.
Accordingly, the reaction of decanol 1 (Table 1, entry 1)
with DMFA (2equiv) and ZrCl4 (10mol%) at room
temperature under solvent free conditions gave 1a
*
Corresponding author. Fax: +91 40 27160387; e-mail: esmvee@
iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.091

9230
G. V. M. Sharma et al. / Tetrahedron Letters 45 (2004) 9229–9232
Table 1. ZrCl4 (10mol%) catalysed preparation of MOM ethers
Entry
1
Starting material
Product
Time (h)
4
Yield (%)
96
CH3(CH2)8CH2OH
1
CH3(CH2)8CH2OMOM
1a
OMOM
OH
2
3
1
2
97
96
2
2a
OH
OMOM
3a
3
OMOM
OH
4
5
6.5
97
94
4
4a
7
OH
OMOM
5
5a
OH
OMOM
O
O
O
6
7
8
5
93
94
93
O
O
O
O
O
O
O
6a
6
O
O
O
O
O
O
O
OMOM
OMe
OH
6.5
O
O
O
7a
7
O
O
OMe
MOMO
HO
5
O
O
O
O
8
8a
9
TPSOCH2(CH2)2CH2OH
9
TPSOCH2(CH2)2CH2OMOM
9a
3.5
5
98
95
)
(
)
2
(
2
PMBO
OH
PMBO
OMOM
10
10a
10
11
12
CH3(CH2)8CH2OTBDMS
11
CH3(CH2)8CH2OMOM
6
5
96
97
11a
CH3(CH2)8CH2OMOM
12a
CH3(CH2)8CH2OTHP
12
(96%) in 4h. However, benzylic alcohols 2 and 3 (Table
1, entries 2 and 3) gave the respective products 2a (97%)
and 3a (96%) more quickly (1 and 2h). Similarly, nopol
4 and menthol 5 (Table 1, entries 4 and 5) underwent
smooth reaction to give 4a (97%) and 5a (94%), respec-
tively, wherein formation of 5a took longer (7h). In a
further study, the sugar substrates 6, 7 and 826 contain-
ing acid sensitive isopropylidene groups as well as an
anomeric methoxy group (8) were unaffected under the
above reaction conditions and gave 6a (93%), 7a (94%)
and 8a (93%), respectively.
facile MOM protection to give the MOM ethers 9a
(98%) and 10a (95%) as indicated in Table 1. However,
substrates 1127 and 1228 with TBS and THP ether
groups on reaction with DMFA and ZrCl4 (10mol%)
underwent a one-pot deprotection and conversion to
give the MOM ethers 11a (96%) and 12a (97%), respec-
tively. This study thus infers that TPS, PMB and aceto-
nide groups survive the reaction conditions along with
substrates such as sugars/terpenes, while TBS and
THP are not compatible and were converted into
MOM ethers in one pot.
Having established the reaction conditions for MOM
protection on a variety of substrates, the study was then
extended to other alcohols with acid sensitive protecting
groups. Thus, alcohols 9 and 10 (Table 1, entries 9 and
10) with TPS and PMB groups, respectively, underwent
3. Deprotection of (MOM) ethers using ZrCl4 (50mol%)
MOM ether 2a when treated with 20mol% ZrCl4 in iso-
propanol at room temperature, gave 2 (Table 2, entry 1)

G. V. M. Sharma et al. / Tetrahedron Letters 45 (2004) 9229–9232
Table 2. ZrCl4 (50mol%) catalysed deprotection of MOM ethers
9231
Entry
Starting material
Product
Time (h)
1
Yield (%)
OH
OMOM
1
97
97
2a
2
2
3
CH3(CH2)8CH2OMOM
1a
CH3(CH2)8CH2OH
1
4
4
OH
OMOM
93
93
4a
4
O
OCH3
O
OCH3
MOMO
HO
4
5
O
O
O
O
8a
8
5
6
TPSOCH2(CH2)2CH2OMOM
9a
TPSOCH2(CH2)2CH2OH
9
3.5
4.5
97
94
(
)
(
)
PMBO
2
O
2
OH
PMBO
10
10a
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in 92% yield in 24h, while at reflux, the reaction was
complete in 11h to give 2 in 90% yield. However, with
50mol% ZrCl4, the reaction with 2a was complete in
1h and gave 2 in 97% yield. Further, the reaction of
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(93%), while, substrates 9a and 10a containing TPS
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(94%), wherein the TPS and PMB groups were found
to be intact.
In conclusion, mild and efficient protocols for the prep-
aration of MOM ethers using ZrCl4 (10mol%)29
and deprotection of MOM ethers with ZrCl4 (50
mol%)30 have been established. The study also demons-
trated that acid sensitive groups and substrates such
as sugars and terpenes are unaffected by the present
reagent system. THP and TBS ethers were converted
in one pot into MOM ethers taking advantage of their
vulnerability to ZrCl4. Thus the above reaction condi-
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the protection and deprotection of MOM ethers and
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Delhi, for the award of fellowships.
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ised by 1H NMR, IR and mass spectroscopy. Spectral
data: 7a: [a]D ꢀ23.33 (c 1.50, CHCl3); H NMR (CDCl3,
1
400MHz): d 1.35 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.45 (s,
3H, CH3), 1.50 (s, 3H, CH3), 3.35 (s, 3H, –OCH3), 3.70 (d,
1H, J = 2.2Hz, H-6), 3.80 (d, 1H, J = 2.2Hz, H-60), 3.90–
4.05 (m, 3H, H-3, H-4, H-5), 4.25 (d, 1H, J = 2.28Hz, H-
50), 4.40 (s, 1H, H-2), 4.64 (d, 1H, J = 6.09Hz, Ha), 4.68
(d, 1H, J = 6.09Hz, Hb); FABMS (m/z): 303 (M+ꢀ1) (8),
289, 215, 85, 44; IR (neat): 2914, 1612, 1464, 1248, 1174,
1096cmꢀ1; 10a: 1H NMR (CDCl3, 300MHz): d 1.65 (q,
2H, J = 7.5Hz, CH2), 2.15 (q, 2H, J = 7.96Hz, CH2), 3.30
(s, 3H, –OCH3), 3.40 (t, 2H, J = 6.42Hz, CH2), 3.80 (s,
3H, –OCH3), 3.95 (d, 2H, J = 4.91Hz, CH2), 4.40 (s, 2H,
CH2), 4.60 (s, 2H, CH2), 5.50–5.70 (m, 2H, olefinic), 6.80
(d, 2H, J = 8.68Hz, Ar–H), 7.20 (d, 2H, J = 8.68Hz, Ar–
H); EIMS: 280 (M+), 236, 205, 156, 107, 91; IR (neat):
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29. General experimental procedure for the protection of
MOM ethers: To a solution of alcohol (1mmol) in DMFA
(2mmol), ZrCl4 (0.1mmol) was added and stirred at room
temperature until the starting material completely disap-
peared (TLC analysis). The reaction mixture was treated
with EtOAc (20mL), washed with water (15mL), brine
(15mL), dried (Na2SO4) and evaporated under reduced
pressure to give the MOM ethers, which were character-
2985, 2954, 1617, 1513, 1337, 1214, 1075cmꢀ1
.
30. General experimental procedure for the deprotection of
MOM ethers: A mixture of MOM ether (1mmol) and
ZrCl4 (0.5mmol) in dry isopropanol (4mL) was heated at
reflux. After the completion of reaction (TLC analysis), it
was cooled to room temperature, the solvent was removed
under reduced pressure and the residue was treated with
EtOAc (10mL). The organic layer was washed with water
(10mL), brine (10mL), dried (Na2SO4) and evaporated
under reduced pressure to give the products. Spectral data
for 10: 1H NMR (CDCl3, 300MHz): d 1.65 (q, 2H,
J = 7.0Hz, CH2), 2.15 (q, 2H, J = 7.5Hz, CH2), 3.40 (t,
2H, J = 5.5Hz, CH2), 3.80 (s, 3H, –OCH3), 3.95 (d, 2H,
J = 8.6Hz, 1H), 4.40 (s, 2H, CH2), 5.50–5.70 (m, 2H,
olefinic), 6.80 (d, 2H, J = 8.7Hz, Ar–H), 7.20 (d, 2H,
J = 8.7Hz, Ar–H); EIMS: 250 (M+), 204, 156, 107, 91; IR
(neat): 2976, 2947, 1622, 1517, 1341, 1221, 1081cmꢀ1
.