Anhydrous FePO4 as a cost-effective and recyclable catalyst for tetrahydropyranylation and tetrahydrofuranylation of alcohols and phenols

Article abstract of DOI:10.2174/157017811796064485

In this article, a mild and efficient protocol for the tetrahydropyranylation and tetrahydrofuranylation of various aliphatic and benzylic alcohols and phenols into their corresponding THP and THF ethers (with 3,4-dihydro- 2H-pyran, DHP and 2,3-dihydrofuran, DHF) has been developed using a catalytic amount of anhydrous FePO₄ at room temperature and relatively short reaction times in good to excellent yields.

Full text of DOI:10.2174/157017811796064485

Letters in Organic Chemistry, 2011, 8, 431-435
431
Anhydrous FePO4 as a Cost-Effective and Recyclable Catalyst for
Tetrahydropyranylation and Tetrahydrofuranylation of Alcohols and
Phenols
Farahnaz K. Behbahani* and Mona Farahani
Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran
Received November 18, 2010: Revised March 18, 2011: Accepted April 18, 2011
Abstract: In this article, a mild and efficient protocol for the tetrahydropyranylation and tetrahydrofuranylation of various
aliphatic and benzylic alcohols and phenols into their corresponding THP and THF ethers (with 3,4-dihydro- 2H-pyran,
DHP and 2,3-dihydrofuran, DHF) has been developed using a catalytic amount of anhydrous FePO4 at room temperature
and relatively short reaction times in good to excellent yields.
Keywords: Alcohols, anhydrous FePO4, deprotection , phenols, protection , THF ethers, THP ethers.
INTRODUCTION
expensive catalysts or low reactivities. In addition, some of
these catalysts cannot be recovered and reused.
The protection-deprotection of hydroxyl groups is
preeminent importance in multi-step organic synthesis. THP
ethers are one of the most useful protective groups in multi-
stage synthesis, due to the remarkable stability under neutral
and basic conditions, and are resistant to oxidizing and
reducing agents such as hydrides, alkylating reagents,
Grignard reagents and organometallic reagents [1]. Their
sensitivity to acidic deprotection allows orthogonal
protecting groups strategies to be employed [2] but their co-
use with other acid-sensitive groups remains problematic.
The structurally similar but less described tetrahydrofuranyl
ethers (using 2,3-dihydrofuran, DHF) are also important and
have been utilized in hydroxyl groups' protection [3].
Deprotection of THP ethers for regeneration of hydroxyl
compounds usually entails rather harsh acidic conditions
which are rarely compatible with sensitive substrates [7].
In recent years, anhydrous FePO4 has gained importance
as versatile reaction medium for effectting various organic
transformations sush as selective oxidation of CH4 to
CH3OH [27] and benzene to phenol [28], one-pot synthesis
of dihydropyrimidinones and thiones [29] and synthesis of
triarylated imidazoles [30] as
a
catalyst. In this
communication we wish to report that anhydrous FePO4 is
also excellent and efficient catalyst to perform tetrahydro-
pyranylation/tetrahydrofuranylation in dichloromthane and
deprotection in methanol at room temperature (Scheme 1).
THP ethers can be extensively prepared from a variety of
hydroxyl containing compounds with 3,4-dihydro-2H-pyran
(DHP). Recently, a remarkable advance in catalysts used for
the tetrahydropyranylation of alcohols and phenols has been
reported. These include I2 [4], zeolite [5], water [6], PdCl2
(CH3CN)2 [7], trichloroisocyanuric acid (TCCA) [8],
Bi(OTf)3.4H2O [9], SnCl2.H2O [10], H14[NaP5W30O110] [11],
2,4,6-trichloro[1,3,5]triazine [12], Fe(HSO4)3 [13],
FePO4/CH2Cl2
ROH
+
or
RO
RO
or
O
FePO4/MeOH
O
O
O
Scheme 1.
RESULTS AND DISCUSSION
Benzyltriphenylphosphonium tribromide [14], Fe(ClO4)3
[15], Al(OTf)3 [16], I2-insitu (Fe(NO3)3 · 9 H2O/NaI) [17],
copper nitrate/acetic acid [18], copper p-toluenesulfonate/
acetic acid [19], acetyl chloride [20], activated carbon
supported sulfuric acid [21] and boric acid [22], whereas
THF ethers were achieved using the p-TsCl/NaH/THF
system [23], CrCl2 [24], ceric ammonium nitrate [25] and
recently with alkylperoxy-ꢀ3-iodane [26]. Most of these are
proved to be efficient for organic reactions. However, some
of these methods have several drawbacks such as harsh
reaction conditions (extreme pH, high reaction temperature),
In our first efforts for preparation of THP ethers we
treated benzyl alcohol with DHP and 2 mol% of FePO4
under solvent-free conditions. The desired THP ether was
formed in low yield and found that the transformation was
very slow under solvent-free conditions. However, several
solvents were examined to standard reaction conditions
(Table 1) and dichloromethane (DCM) as a solvent was
chosen for the reaction at room temperature (entry 5, Table
1) that ensured clean conversion to the desired THP ether in
high yield.
Treatment of various other alcohols and phenols in this
way (Table 2) provided efficient access to the THP ethers.
The protection is useful for primary and secondary alkanols
as well as a range of phenols and is highly efficient in DHP
and DHF due to just 1.1 equiv of these reagents are used per
OH group.
*Address correspondence to this author at the Department of Chemistry,
Karaj Branch, Islamic Azad University, Karaj, Iran; Tel: +98 0261 4418145;
Fax: 0261 4418156; E-mail: Farahnazkargar@yahoo.com
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

432 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Behbahani and Farahani
Table 1. Varying of the Solvents for Preparation of 2-(benzyloxy)-tetrahydro-2H-pyran
Entry
Solvent
Time (h)
Yield (%)a
1
2
3
4
5
Solvent free
Diethyl ether
24
24
12
24
4.0
15
35
40
30
90
Carbon Tetrachloride
Toluene
Dichloromethane
aYields refered to GC.
Table 2. Conversion of Alcohols and Phenols into their Corresponding THP and THF Ethers Using Anhydrous FePO4. All
Reactions were Conducted in DCM and all Reaction Times were Determined by TLC(Conversion 100%)
Yield (%)a
Substrate
Product
Entry
Time (h)
1
4.0
90
OH
OTHP
2
6.0
81
OH
OTHP
OH
OTHP
O
O
3
4
7.0
5.5
86
96
OH
OTHP
OH
OTHP
OTHP
5
6
2.5
3.0
80
92
OH
7
8
4.0
4.0
97
90
OH
OTHP
OH
OTHP
O
O
9
8.0
8.0
95
92
OH
OTHP
10
O
O
HO
THPO
OH
OTHP
11
12
6.0
2.0
83
88
OH
OTHP

FePO4 as a Cost-Effective and Recyclable Catalyst
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
433
(Table 2). Contd…..
Yield (%)a
Substrate
Entry
Product
Time (h)
13
5.0
80
OH
OTHF
OTHF
OH
14
4.5
2.0
82
90
OH
OTHF
15
16
8.0
3.0
84
85
O
O
HO
THFO
OH
OH
17
OH
OTHP
aYields referred to GC.
All types of alcohols (primary, secondry, tertiary,
benzylic, allylic and propargylic) were easily converted to
THP/THF ethers by treatment of 3,4-dihydro-2H-pyran and
2,3-dihydrofuran with catalytic amounts of anhydrous FePO4
in DCM at ambient temperature (Table 2).
The deprotection of THP ethers can be carried out under
similar mild reaction conditions and with the same ease as
the protection process in good to excellent yields. The results
of the selected examples are illustrated in Table 3.
Although there are several reports on the formation of
THF ethers, to the best of our knowledge rarely of the
reported protocols involve Lewis acid catalysts [16]. The
broader generality of our method was thus explored by
successfully synthesizing THF ethers. The alcohols listed in
Table 2 were treated under the standard conditions described
above to produce the corresponding THP ethers.
Accordingly, primary and secondary benzyl alcohols
undergo tetrahydropyranylation in 81-90 yields (entries 1-3,
Table 2). In addition to benzylic alcohols, this catalyst is
effective for the variety of aliphatic alcohols (entries 4-6, 12,
15; Table 2). Primary alcohols protected within less time
than secondary and tertiary alcohols. The longer reaction
time could be due to the steric effect exerted by bulky
groups. It is very interesting to note that tertiary and
secondary alcohols such as t-butanol can also be protected
with satisfactory yield and there was no elimination product
in the reaction mixture.
In order to show the merits of this catalytic method in
comparison with those of reported protocols, we compiled
the results of the formation of 2-(benzyloxy)-tetrahydro-2H-
pyran (Entry 1, Table 2) in the presence of a variety of iron
(III) salts and complexes. From the results given in Table 4,
the advantages of our method are evident, regarding the
catalyst amounts, heterogeneous and recyclable of the
catalyst, a lack of the nitrate and perchlorate (entry 1, 3;
Table 4) and shorter reaction time (entry 4) which are very
important in chemical industry and from green chemistry
point of view especially when it is combined with easy
separation.
Of various naphthols studied, only 2-naphthol furnished
THP ether with high yield where as substituted naphthols
either with electron withdrawing or electron-releasing
substituent did not react at all. In order to survey
chemoselectivity of this transformation, 3-, 4-hydroxy
benzaldehydes were subjected as substrates. It was found
that C=O group was not involved in reaction and remain
intact (entries 9, 10, Table 2). FePO4 also did not affect on
either double or triple bond of allylic and propargylic
alcohols (entries 7 and 8) and could be perfectly used to
catalyze the protection and deprotection of aliphatic alcohols
where as dehydration of aliphatic alcohols was reported
under acidic condition [31] (entry 4-6, Table 2). It is
noteworthy that under these conditions no oxidation of
alcohols and even benzylic alcohols (entry1) was observed.
Although FePO4 has been known as oxidant to convert CH4
to CH3OH [15], in this reaction behaves solely as a powerful
and highly selective Lewis acid. As a natural product,
menthol was subjected in this reaction and afforded the
corresponding THP ether in high yield (entry 15, Table 2). In
the end, THP ethers on primary alcohol groups were
selectively formed from dihydroxy alcohols(entry 17, Table
2).
EXPERIMENTAL
Protection of hydroxy Groups Catalyzed by FePO4.
Typical Procedure
Ferric phosphate (0.015 g, 2.0 mol%) in DCM (1 ml),
DHP (0.46 g, 5.5 mmol) and benzyl alcohol (0.54 g, 5 mmol)
were mixed at room temperature. The progress of the
reaction
was
monitored
by
TLC
(eluent:
n-
hexane:ethylacetate, 4:1). Upon completion of the reaction,
mixture of the reaction was passed through of silica gel and
washed using n-hexane as an eluent. After drying and
evaporating of solvent, the product obtained in high yield
and physical and spectroscopy data compared with those of
authentic samples.

434 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Behbahani and Farahani
Table 3. Deprotection of THP and THF Ethers Using Anhydrous FePO4. All Reactions were Conducted in Methanol
Yield (%)a
Substrate
Product
Entry
Time (h)
1
4.0
94
OTHP
OH
2
2.5
91
OTHP
OH
OTHP
OH
O
O
3
4
3.0
4.0
82
90
OTHP
OH
OTHP
OTHP
OH
5
6
2.0
3.0
80
85
OH
7
8
2.5
2.0
86
84
OTHP
OH
OTHP
OH
OH
OTHP
9
2.0
88
O
O
10
11
4.0
4.0
81
80
OTHP
OH
O
O
THPO
HO
OTHP
OH
12
13
3.0
92
4.0
4.0
90
85
OTHF
OTHF
OH
OH
14
aYields referred to GC.
Table 4. Comparison the Effect of Varying iron (III) Salts in Preparation of 2-(benzyloxy)-tetrahydro-2H-pyran
Entry
Catalyst
Catalyst (mol%)
Time (h)
Solvent
Yield (%)
Ref.
1
2
3
4
5
Fe(ClO4)3
Fe2(SO4)3.X H2O
Fe(NO3)3.9H2O/ Na I
FeCl3.6H2O / Na I
FePO4
3.0
1.0
1.5/r.t
1.0/r.t
5.0/r.t
12/ r.t
5.0/ r.t
Et2O
-
98
95
96
95
93
[15]
[32]
1.5/2.6
-
DCM
DCM
DCM
[32]
[18]
2.0
This work

FePO4 as a Cost-Effective and Recyclable Catalyst
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
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