Highly efficient and selective methoxymethylation of alcohols and phenols catalyzed by reusable ZrO(OTf)2 under solvent-free conditions

Article abstract of DOI:10.1007/s00706-010-0310-8

Different primary, secondary, and tertiary alcohols were efficiently converted to their corresponding methoxymethyl ethers with formaldehyde dimethyl acetal in the presence of catalytic amounts of ZrO(OTf)₂ at room temperature. Phenols were als

Full text of DOI:10.1007/s00706-010-0310-8

Monatsh Chem (2010) 141:641–647
DOI 10.1007/s00706-010-0310-8
ORIGINAL PAPER
Highly efficient and selective methoxymethylation of alcohols
and phenols catalyzed by reusable ZrO(OTf) under
solvent-free conditions
2
Majid Moghadam
Valiollah Mirkhani
Mostafa Khajehzadeh
•
Shahram Tangestaninejad
•
•
Iraj Mohammadpoor-Baltork
•
Received: 8 July 2009 / Accepted: 18 March 2010 / Published online: 16 April 2010
Ó Springer-Verlag 2010
Abstract Different primary, secondary, and tertiary alco-
hols were efficiently converted to their corresponding
methoxymethyl ethers with formaldehyde dimethyl acetal in
agents [2, 3]. Methoxymethyl (MOM) ethers are frequently
prepared by the reaction of alcohols or phenols with
formaldehyde dimethyl acetal (FDMA). The main disad-
vantage of FDMA is its low methoxymethylating power in
the absence of a suitable catalyst. To solve this problem a
number of catalysts such as LiBr/Tos-OH [4], P O [5],
the presence of catalytic amounts of ZrO(OTf) at room
2
temperature. Phenols were also methoxymethylated by this
catalytic system. Advantages of using this catalytic system
are the short reaction times, easy catalyst preparation, high
product yield, solvent-free conditions, applicability for both
alcohols and phenols, and reusability of the catalyst.
2
5
p-toluenesulfonic acid [6], Nafion-H [7], TMSI [8], BF3
[9], Envirocat [10], [Sn(IV)(Br TPP)(OTf) ] [11], expan-
8
2
sive graphite [12], sulfated metal oxides [13], silica sulfuric
acid [14], Sc(OTf)3 [15], Bi(OTf)3 [16], ZrCl4 [17],
MoO (acac) [18], H PMo O [19], anhydrous FeCl
Keywords Methoxymethylation Á Alcohol Á Phenol Á
Zirconyl triflate Á Formaldehyde dimethyl acetal
2
2
3
12 40
3
2
-
˚
dispersed on 3 A molecular sieve [20], TiO /SO
[21],
2
4
H PW O [22], and H PW O supported on silica and
12 40
3
12 40
3
zirconia [23] have been reported. However, some of the
reported methods suffer from one or more disadvantages
such as harsh reaction conditions, high reaction tempera-
ture, long reaction times, high cost or toxicity of the
reagents, inapplicability for phenolic OH, and tedious
work-up. Consequently, introduction of efficient and
selective methods for the preparation of methoxymethyl
ethers using inexpensive, relatively non-toxic, easily han-
dled, and environmentally friendly catalysts is of practical
importance and is still in demand.
Introduction
The protection of hydroxyl groups of alcohols and phenols
has occupied a unique position in organic synthesis
because of the fundamental importance of hydroxyl groups
in multistep synthesis of polyfunctional molecules such as
nucleosides, carbohydrates, steroids, and natural products
[
1]. Methoxymethylation of these functional groups is a
commonly used protective process for alcohols and phenols
in organic synthesis. These protecting groups provide a
number of significant advantages such as ease of intro-
duction and stability toward a wide variety of conditions
including many organometallic, reducing, and oxidizing
Zirconium(IV) salts have recently attracted much
attention due to their low cost, high catalytic activity, easy
availability, and low toxicity [24, 25]. A variety of Zr(IV)
salts has been used for several organic transformations such
as Friedel–Crafts reaction [26], Diels–Alder reaction [27],
Michael reaction [28], acetalization of carbonyl com-
pounds [29–31], conversion of nitriles to oxazolines and
imidazolines [32, 33], and trimethylsilylation of alcohols
and phenols [34].
M. Moghadam (&) Á S. Tangestaninejad Á V. Mirkhani Á
I. Mohammadpoor-Baltork Á M. Khajehzadeh
Catalysis Division, Department of Chemistry,
University of Isfahan,
81746-73441 Isfahan, Iran
e-mail: moghadamm@sci.ui.ac.ir
Here, we report the highly efficient methoxymethylation
of alcohols and phenols with FDMA catalyzed by reusable
ZrO(OTf) at room temperature (Scheme 1).
2
123

6
42
M. Moghadam et al.
O
O
This catalyst was successfully applied for methoxyme-
thylation of phenols with FDMA and the corresponding
ethers were obtained in excellent yields. As with alcohols
the reactions were completed for all phenols in 10–15 min
R
Me
Me
R
OH
or
Ar OH
ZrO(OTf)2
FDMA
or
Ar
(Table 3).
O
O
In order to check the chemoselectivity of the present
Scheme 1
method, a set of competitive reactions was conducted
between primary or secondary and tertiary alcohols or
phenols (Table 4). The results indicated that the present
protocol is potentially applicable for the chemoselective
conversion of primary and secondary or tertiary alcohols
to their MOM ethers in the presence of phenols and
alcohols.
Results and discussion
The catalytic ability of different zirconium salts was
investigated in the methoxymethylation of 4-chlorobenzyl
alcohol. In this manner, 4-chlorobenzyl alcohol was reac-
ted with FDMA in the presence of 2.5 mol% of ZrCl4,
ZrOCl Á8H O, and ZrO(OTf) . The results (Table 1)
In order to show the effectiveness of the presented
method in the methoxymethylation of hydroxyl com-
pounds, the results obtained in the methoxymethylation of
2
2
2
benzyl alcohol catalyzed by ZrO(OTf) were compared
2
showed that ZrO(OTf) is more efficient than the others
2
with some of those reported in the literature (Table 5). The
results showed that our method is superior in terms of
catalyst amount, reaction time, or product yield.
and was therefore used as an efficient catalyst for meth-
oxymethylation of alcohols and phenols with FDMA.
The optimized conditions obtained for methoxymethy-
lation of 4-chlorobenzyl alcohol were alcohol, FMDA, and
catalyst in a molar ratio of 40:7:1. Under the same condi-
tions a wide variety of primary, secondary, and tertiary
alcohols were subjected to methoxymethylation with
FDMA in the presence of catalytic amounts of ZrO(OTf)2
at room temperature. The results which are summarized in
Table 2 showed that all primary, secondary, and tertiary
alcohols including aromatic, aliphatic, and cyclic ones
were completely converted efficiently to their correspond-
ing methoxymethyl ethers in 5–20 min. In the case of
aromatic alcohols, the nature of substituents has no sig-
nificant effect on the methoxymethylation yield. No
dehydration product was observed in the case of tertiary
alcohols.
The reusability of the catalyst was monitored in the
multiple methoxymethylation of 4-chlorobenzyl alcohol.
After each consecutive run, the solvent was evaporated and
the catalyst was filtered off and washed with Et O and
2
CH Cl successively and used in the next run, using fresh
2
2
alcohol and FDMA. The results showed that after reusing
the catalyst for four runs no significant loss of its activity
was observed.
In conclusion, we showed that different primary, sec-
ondary, and tertiary alcohols as well as phenols could be
efficiently converted to their corresponding methoxymethyl
ethers (MOM ethers) with formaldehyde dimethyl acetal
(
FDMA) in the presence of catalytic amounts of ZrO(OTf)2
at room temperature. The advantages of using this catalytic
system are the short reaction times, easy preparation of
catalyst, high product yield, solvent-free conditions,
applicability for both alcohols and phenols, and reusability
of the catalyst.
The actual mechanism of these reactions is not truly
clear, but due to the strong interaction between Zr and
oxygen it seems that first an oxonium ion 1 is formed via
activation of FDMA by ZrO(OTf) . The alcohol attacks 1
2
to give 2 which in turn converts to the methoxymethylated
product 3 and releases the catalyst for the next catalytic
cycle (Scheme 2).
Experimental
All materials were purchased from Merck. All products
were identified by comparison of their physical and spec-
1
tral data with those of authentic samples. H NMR spectra
Table 1 Investigation of the catalytic activity of different zirconium
salts in the methoxymethylation of 4-chlorobenzyl alcohol with
FDMA
Catalyst
Catalyst amount
mg, mol%)
Time (min)
Yield (%)
were recorded in a CDCl3 solution on a Bruker-AC
(
500 MHz spectrometer. IR spectra were recorded on a
Shimadzu IR-435 spectrophotometer. Melting points were
determined using a Stuart Scientific SMP2 apparatus.
ZrO(OTf)
2
10 (2.5)
5 (2.5)
8 (2.5)
10
10
10
100
45
0
ZrCl
4
ZrO(OTf) was prepared and characterized according to
2
ZrOCl
2
our previously reported procedure [34].
1
23

Highly efficient and selective methoxymethylation of alcohols and phenols
643
2
Table 2 Protection of alcohols with FDMA catalyzed by ZrO(OTf) at room temperature
a
Entry
1
ROH
ROMOM
Time (min)
10
Yield (%)
97
Ref.
[35]
3a
OH
2
3
4
3b
3c
3d
5
5
96
96
97
–
OH
OH
OH
Me C
3
[14]
MeO
15
–
Cl
Br
5
6
7
3e
3f
15
10
5
98
95
96
[14]
[35]
[35]
OH
OH
OH
O N
2
3g
8
9
3h
3i
5
95
97
[36]
[14]
OH
15
Me
OH
1
0
3j
5
94
[12]
OH
123

6
44
M. Moghadam et al.
Table 2 continued
a
Entry
ROH
ROMOM
Time (min)
15
Yield (%)
Ref.
[14]
1
1
3k
97
Me
Me
OH
1
1
2
3
3l
10
20
93
95
[36]
Me
Me
C
OH
Me
3m
[14]
OH
1
1
a
4
5
3n
3o
10
10
94
93
[12]
[35]
OH
OH
Isolated yields
General procedure for the methoxymethylation
of alcohols and phenols at room temperature
-
ZrO(OTf)2
O
+
O
H C
C
H
CH3
3
ROH
To a solution of alcohol or phenol (1 mmol) in FDMA
7 mmol), 0.01 g ZrO(OTf) (2.5 mol%) was added and
2
(
2
1
H C
3
the mixture was stirred at room temperature for the
appropriate time according to Table 2. The progress of the
reaction was monitored by TLC (eluent cyclohexane/ethyl
O
MeOH
H C
2
O
acetate, 4:1). After completion of the reaction, the excess
3
FDMA was evaporated and 10 cm Et O was added and
H C
-
3
ZrO(OTf)2
2
the catalyst was filtered. The filtrate was evaporated and
the crude product was purified by column chromatography
on silica gel (eluent cyclohexane/ethyl acetate, 4:1) to
afford the pure product.
ZrO(OTf)2
O
+
O
R
C
H
CH3
2
2
Catalyst reusability
ROCH OCH3
2
The reusability experiments were carried out as follows:
3
0.03 g ZrO(OTf) (2.5 mol%) was added to a solution of
2
Scheme 2
benzyl alcohol (3 mmol) in FDMA (21 mmol) and the
1
23

Highly efficient and selective methoxymethylation of alcohols and phenols
645
2
Table 3 Protection of phenols with FDMA catalyzed by ZrO(OTf) at room temperature
a
Entry
1
ArOH
ArOMOM
Time (min)
10
Yield (%)
96
Ref.
[36]
3p
OH
2
3
3q
3r
10
15
97
95
[37]
[37]
Cl
OH
OH
OH
Cl
4
3s
15
94
[36]
OMe
5
6
3t
10
15
96
96
[36]
[37]
O N
OH
2
3u
OH
CH3
7
3v
10
97
[37]
OH
H C
3
a
Isolated yield
mixture was stirred at room temperature for 10 min. After
3H, OCH
4.76 (s, 2H, ArCH
(d, J = 8.20 Hz, 2H, Ar) ppm.
3
), 1.34 (s, 9H, C(CH
) ), 4.60 (s, 2H, OCH O),
3 3 2
the reaction was completed, the excess FDMA was evap-
3
orated and 30 cm Et O was added. The catalyst was
2
), 7.31 (d, J = 8.16 Hz, 2H, Ar), 7.40
2
filtered, dried at 50 °C, and used in the subsequent run.
4
-Chloro-1-(methoxymethoxy)methylbenzene
(3d, C Cl)
Mp 70–72 °C; IR (KBr): ꢀm = 2,900, 1,315, 1,285, 1,100,
4
-tert-Butyl-1-(methoxymethoxy)methylbenzene
3b, C H O )
H O
9 11 2
(
1
3 20 2
-
1 1
Oil; IR (KBr): ꢀm = 2,900, 1,365, 1,090, 1,030, 755,
845, 760 cm ; H NMR (500 MHz, CDCl
3H, OCH ), 4.54 (s, 2H, OCH O), 4.74 (s, 2H, ArCH
2
): d = 4.16 (s,
3
-
1
1
7
00 cm
;
H NMR (500 MHz, CDCl ): d = 4.18 (s,
3
2
),
3
123

6
46
M. Moghadam et al.
Table 4 Selective
Row
1
ROH
Time (min)
15
Yield (%)
97
methoxymethylation of alcohols
and phenols catalyzed by
ZrO(OTf)
2
Cl
CH OH
2
1
5
0
OH
2
15
97
0
Cl
CH OH
2
1
5
Me
Me
OH
3
15
97
0
Cl
CH OH
2
1
5
OH
4
15
97
OH
CH3
1
5
0
OH
5
15
97
Me
Me
OH
1
5
0
OH
1
23

Highly efficient and selective methoxymethylation of alcohols and phenols
647
Table 5 Comparison of the results obtained for the methoxymethylation of benzyl alcohol catalyzed by ZrO(OTf)
other catalysts
2
with those obtained by using
Catalyst
OH
OCH OCH
2
3
Entry
Catalyst
Catalyst (mol%)
Temperature
Time (h)
Yield (%)
Ref.
1
2
3
4
5
6
7
8
9
ZrO(OTf)
2
2.5
20 mg
50 mg
200 mg
5
RT
0.16
6
96
91
91
85
98
95
97
85
90
90
92
91
94
84
–
Expansive graphite
Sulfated metal oxides
Silica sulfuric acid
Reflux
RT
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[23]
3
Reflux
Reflux
Reflux
RT
1.5
3
Sc(OTf)
3
Bi(OTf)
ZrCl
MoO
3
5
1
4
10
1
2
(acac)
2
2
Reflux
Reflux
RT
4
H PMo12O
3
40
5
3
˚
dispersed on 3 A molecular sieves
10
11
12
13
14
Anhydrous FeCl
3
90
1
2
4
-
TiO
2
/SO
20
Reflux
RT
6
H PW12
3
H PW12
3
H PW12
3
O
40
0.4
0.4
0.4
3
O
O
40 on silica
RT
1
40 on zirconia
RT
2.5
RT room temperature
7
.30 (d, J = 7.44 Hz, 2H, Ar), 7.35 (d, J = 6.42 Hz, 2H,
Ar) ppm.
18. Kantam ML, Santhi PL (1993) Synlett 429
1
2
2
9. Zolfigol MA, Shiri M (2005) Mendeleev Commun 165:165
0. Patney HK (1992) Synlett 567
1. Jin TS, Guo JJ, Yin YH, Zhang SL, Li TS (2002) J Chem Res (S)
88
Acknowledgments We are thankful to the Center of Excellence of
Chemistry of University of Isfahan (CECUI) for financial support of
this work.
1
2
2
2. Mohammadpoor-Baltork I, Moghadam M, Tangestaninejad S,
Mirkhani V, Mirjafari A (2008) Can J Chem 86:831
3. Mohammadpoor-Baltork I, Moghadam M, Tangestaninejad S,
Mirkhani V, Mirjafari A (2008) Polyhedron 27:2612
24. Firouzabadi H, Jafarpour M (2008) J Iran Chem Soc 5:159
References
2
2
5. Bora U (2003) Synlett 1073
6. Heine HW, Cottle DL, Van Mater HL (1946) J Am Chem Soc
1
2
. Schelhaas M, Waldmann H (1996) Angew Chem Int Ed 35:2056
. Greene TW, Wuts PGM (1991) Protective groups in organic
synthesis. Wiley, New York
. Kocienski PJ (1994) Protecting groups. Thieme, Stuttgart
. Gras JL, Chang YYKW, Guerin A (1985) Synthesis 74
. Fuji K, Nakano S, Fujita E (1975) Synthesis 276
. Yarley JP, Fletcher H (1976) Synthesis 244
. Olah GA, Husain A, Gupta BGB, Narang SC (1981) Synthesis 471
. Olah GA, Husain A, Narang SC (1983) Synthesis 896
. Danheiser RL, Romines KR, Koyama H, Gee SK, Johnson CR,
Medich JR (1992) Org Synth 71:133
6
8:524
7. Evans DA, Chapman KT, Bisaha J (1988) J Am Chem Soc
10:1238
2
1
3
4
5
6
7
8
9
2
2
3
3
8. Smitha G, Patnaik S, Reddy CS (2005) Synthesis 711
9. Firouzabadi H, Iranpoor N, Karimi B (1999) Synlett 319
0. Firouzabadi H, Iranpoor N, Karimi B (1999) Synlett 321
1. Moghadam M, Mohammadpoor-Baltork I, Tangestaninejad S,
Mirkhani V, Yazdani P, Ghorjipoor S (2009) Heteroatom Chem
2
0:131
3
3
2. Mohammadpoor-Baltork I, Khosropour AR, Hojati SF (2007)
Catal Commun 8:200
3. Mirkhani V, Mohammadpoor-Baltork I, Moghadam M, Tanges-
taninejad S, Abdollahi-Alibeik M, Kargar H (2007) Appl Catal A
Gen 325:99
4. Moghadam M, Tangestaninejad S, Mirkhani V, Mohammadpoor-
Baltork I, Chahardahcheric S, Tavakoli Z (2008) J Organomet
Chem 693:2041
5. Lee ASY, Hu YJ, Chu SF (2001) Tetrahedron 57:2121
6. Marcune FB, Karady S, Dolling UH, Novak JT (1999) J Org
Chem 64:2446
1
1
0. Bandgar BP, Hajare CT, Wadgaonkar PP (1996) J Chem Res (S) 90
1. Moghadam M, Tangestaninejad S, Mirkhani V, Mohammadpoor-
Baltork V, Khajehzadeh M, Kosari F, Araghi M (2010) Polyhe-
dron 29:238
2. Jin TS, Li TS, Gao YT (1998) Synth Commun 28:837
3. Lin CH, Wan YM, Huang YM (2003) Catal Lett 87:253
4. Niknam K, Zolfigol MA, Khorramabadi-Zad A, Zare R, Shayegh
M (2006) Catal Commun 7:494
5. Karimi B, Ma’mani L (2003) Tetrahedron Lett 44:6051
6. Sreedhar B, Swapna V, Sridhar C (2005) Catal Commun 6:293
7. Sharma GVM, Reddy KL, Lakshmi PS, Krishna PR (2004)
Tetrahedron Lett 45:9229
3
1
1
1
3
3
1
1
1
3
7. Ronald RC, Winkle MR (1983) Tetrahedron 39:2031
123